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Advances in ovarian cancer therapy

Advances in ovarian cancer therapy Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment. Keywords Ovarian cancer · Biological drugs · Targeted therapy · Clinical trials Introduction death signals. These are, e.g., anti-angiogenic factors, inhibi- tors of growth factor signaling, polyADP-ribose polymerase Ovarian cancer is the second most common and the most (PARP) inhibitors, or folate receptor inhibitors. In addition, lethal gynecologic malignancy in the western world. So far, there are many immunotherapeutic approaches tested. So far, there is lack of methods recommended for screening and these new agents and therapeutic approaches were not shown early diagnostics of this disease. As a consequence, and also to cure ovarian cancer, but they may improve therapy and due to the absence of early warning symptoms, about 70% of lead to the delay of recurrence or stabilization of the disease. cases is diagnosed at an advanced stage and have bad prog- However, the landscape of ovarian cancer treatment is nosis. Late-stage ovarian cancer is incurable in the majority complicated by heterogeneity of these tumors. Different of cases, but recently it tends to become a kind of chronic histological types of epithelial ovarian cancer have distinct disease. This is mostly due to the progress in surgical tech- cellular origin, diverse mutational spectrum, and thus, dif- nology and contemporary regimes of systemic treatment, as ferent prognosis (rev. in: [1, 2]). Even within one histological well as some new drugs entering the clinic. type, distinct molecular subtypes with different prognoses Currently, there are also many new drugs under develop- can be found (see e.g.: [3, 4]). To address these issues there ment and tested in the ongoing clinical trials aimed to evalu- is a need to better characterize these differences, find reliable ate their efficacy in the treatment of ovarian cancer. New biomarkers and develop appropriate targeted therapies. Even drugs are mostly directed against molecular targets and path- though many studies are aimed at biomarker discovery, and ways that are indispensable for cancer cells proliferation, many putative biomarkers are published, very few are finally tumor growth and escape from immune surveillance and entering the clinics [5]. In this review, we discuss current standard in the therapy for ovarian cancer and new therapeutic approaches, and their Alexander J. Cortez and Patrycja Tudrej contributed equally. present status. * Katarzyna M. Lisowska katarzyna.lisowska@io.gliwice.pl Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice 44-100, Poland Vol.:(0123456789) 1 3 18 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 by clinical symptoms, it is not recommended to implement Standard treatment for ovarian cancer second-line treatment. Deferral of treatment, until clinical symptoms occur, does not worsen the survival [13]. There The standard treatment for ovarian cancer is maximal is consensus that patients with recurrent disease on the cytoreductive surgical debulking followed by the plat- basis of CA125 alone, are eliglible for clinical trials [14]. inum-based chemotherapy. Confirmation of the diagno- sis, as well as staging of the disease is performed during New approaches to the first‑line treatment surgery. In any case, efforts should be made to define the his- Phase III clinical trials indicate that the incorporation of tological type of the tumor, including grading [6]. High- targeted anti-angiogenic treatment with bevacizumab and grade/low-grade scale is currently used, except for endo- weekly dose-dense paclitaxel into first-line management of metrioid ovarian cancer where a three-grade scale is used ovarian cancer can improve survival. Thus, both of these (G1, G2 or G3) [7]. Staging assessment in surgical-path- approaches can be considered new standards-of-care. How- ologic degrees should be done according to current FIGO ever, they have markedly different economic implications recommendations [8]. and place distinct burdens on patients (higher toxicity and According to the Gynaecologic Oncology group intensity of therapy). (GOG), optimal cytoreduction was previously defined as In 2011, based on data from Gynecologic Oncology residual tumor nodules each measuring 1 cm or less in Group protocol 0218 (GOG0218/NCT00262847) and Inter- maximum diameter. However, large multivariate analysis national Collaboration for Ovarian Neoplasia 7 (ICON7/ showed improved progression-free and overall survival NCT00483782) trials, bevacizumab has gained the Euro- for group of patients with complete resection compared pean Medicines Agency (EMA) approval for the first-line with groups with the so-called optimal (between 0.1 and treatment together with standard chemotherapy (carboplatin 1  cm) and suboptimal cytoreduction (p < 0.0001) [9]. and paclitaxel) in women with advanced epithelial ovarian Thus, according to the 2017 ESGO ovarian cancer surgery cancer, fallopian tube cancer or primary peritoneal cancer guidelines, the aim of the frontline surgery is to achieve (OFPC) [15]. However, FDA has not approved bevacizumab complete resection of macroscopic residuals of the disease for the first-line treatment, so far (decision is expected by (complete cytoreduction) [10]. June 2018). After surgery, patients are treated with the intravenous The results of the Japanese GOG 3016 trial platinum/taxane regimes, every 21  days, for six cycles (NCT00226915) suggested that dose-dense weekly pacli- (first-line chemotherapy). In patients with stage IA/IB and taxel plus carboplatin improved survival compared with with G1/G2 tumors, the chemotherapy can be omitted [6]. the conventional regimen. Median progression-free sur- In advanced stages (III/IV), complete cytoreduction vival (PFS) was longer in the dose-dense treatment group is often not possible. The most common reason is the (28.0 months, 95% CI 22.3–35.4) than in the conventional seizure of small bowel mesentery and the lesions in the treatment group (17.2 months, 15.7–21.1; HR 0.71; 95% liver hilum. Patients with inoperable lesions or due to CI 0.58–0.88; p = 0.0015). Overall survival at 3  years poor performance status are first treated with induction was higher in the dose-dense regimen group (72.1%) than (neoadjuvant) chemotherapy. After three cycles of the in the conventional treatment group (65.1%; HR 0.75, chemotherapy, if there is a response to the treatment, the 0.57–0.98; p = 0.03) [16, 17]. On the contrary, the GOG interval debulking surgery (IDS) can be performed, then 0262 trial (NCT01167712) showed that weekly paclitaxel, chemotherapy is continued, up to six cycles [6]. as compared with conventional regimen, did not prolong Treatment outcome is assessed after the completion PFS among patients with ovarian cancer (14.7 versus of first-line chemotherapy. Evaluation of response to the 14.0 months; HR = 0.89; 95% CI 0.74–1.06; p = 0,18). How- treatment is done based on imaging results and accord- ever, it must be mentioned that 84% of analyzed patients ing to RECIST 1.1 criteria (Response Evaluation Criteria received bevacizumab. Among patients who did not receive In Solid Tumors) [11]. The majority of patients respond bevacizumab, weekly paclitaxel was associated with PFS well to the first-line chemotherapy, achieving complete 3.9 months longer than that observed in the conventional response (CR), however, many will develop recurrence. treatment group (14.2 versus 10.3 months; HR = 0.62; 95% For patients with residual disease < 1  cm, the risk for CI 0.40–0.95; p = 0.03). These results support the benefit recurrence is estimated at 60–70%; for women with large- of weekly paclitaxel plus carboplatin, but in the absence of volume residual disease, the risk is estimated at 80–85% bevacizumab administration [18]. International Collabora- [12]. Therefore, patients with CR should be subjected to tion for Ovarian Neoplasia 8 trial (ICON8/ NCT01654146) periodic controls. Increasing level of CA125 can be an is a randomized, three-arm, phase III study designed to early symptom of recurrence, however, if not accompanied investigate again if weekly chemotherapy is more effective 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 19 than standard chemotherapy. ICON8B is investigating the time to relapse is also used as a determinant of tumor sensi- combination of dose-dense chemotherapy and bevacizumab tivity to platinum. Tumors are categorized as: in a subgroup of women with high-risk stage III–IV ovarian cancer [19]. No results of these trials are published so far. – platinum refractory—when tumor progresses during first- There is also ongoing debate whether neoadjuvant chem- line treatment otherapy and IDS may be superior to the massive primary – platinum resistant—recurrence within 6 months after debulking surgery (PDS) in advanced ovarian cancer. The completion of first-line treatment second approach is related with higher mortality and mor- – partially sensitive—recurrence within 6–12 months bidity while the first one may lead to earlier recurrence and – highly sensitive—recurrence after more than 12 months shorter survival. The results of a European Organization for Research and Treatment of Cancer (EORTC) 55971 trial This classification is commonly used, although it is now (NCT00003636) suggested that patients with stage IIIC and generally appreciated that platinum sensitivity is a contin- less extensive metastatic tumors had higher survival with uum, rather than related to arbitrary time points, and cannot primary surgery, while patients with stage IV disease and be accurately determined by progression-free interval (PFI) large metastatic tumors had better survival with neoadju- alone [14]. vant chemotherapy. For patients who did not meet these Selection of second-line chemotherapy protocol is based criteria, both treatment options led to comparable survival on tumor sensitivity to platinum derivatives. Patients that rates [20]. Two new trials: SUNNY (Study of Upfront Sur- have partially- or highly-sensitive tumors can be treated with gery versus Neoadjuvant Chemotherapy in Patients With platinum in combination with other drugs. These patients Advanced Ovarian Cancer, NCT02859038) and TRUST benefit from multi-drug regimens. Usually carboplatin or (Trial on Radical Upfront Surgery in advanced Ovarian Can- cisplatin is used in combination with paclitaxel or pegylated cer, NCT02828618) were recently started, aimed to com- liposomal doxorubicin (PLD) or gemcitabine (with or with- pare the OS after PDS versus IDS following the neoadjuvant out bevacizumab). For treatment of partially-sensitive recur- chemotherapy in patients with FIGO stage IIIB–IVB OFPC. rences, when platinum is not an option (anaphylaxy to plati- A majority of ovarian cancers are chemosensitive and num compounds), PLD with trabectedin can be used [24]. are confined to the surface of the peritoneal cavity for a As was shown in OVA-301 phase III study (NCT00113607), long time. These features decide that ovarian cancer is a the patients with mutation in BRCA gene have longer PFS good target for intraperitoneal (IP) chemotherapy. A recent and OS with this regimen [25]. Trabectedin alone was tested meta-analysis explored the results from nine randomized in MITO15 phase II trial (NCT01772979) for the treatment controlled clinical trials, assessing 2119 women with pri- for recurrent ovarian cancer patients presenting BRCA muta- mary epithelial ovarian cancer, of any FIGO stage, after PDS tion and/or BRCA-ness phenotype (≥ 2 previous responses [21]. Standard intravenous (IV) chemotherapy was compared to platinum). It was concluded that the signature of ‘repeated with chemotherapy that included a component of IP admin- platinum sensitivity’ identifies patients highly responsive istration. Women were less likely to die if they received an to trabectedin which can be valuable alternative option in IP component to chemotherapy (8 studies, 2026 women; patients who present contraindication to receive platinum HR = 0.81; 95% CI 0.72–0.90). IP component chemotherapy [26]. prolonged the disease-free interval (5 studies, 1311 women; The prognosis in patients refractory or resistant to plati- HR = 0.78; 95% CI 0.70–0.86). There was greater serious num treatment is bad. In this group of patients, no benefit toxicity with regard to gastrointestinal effects, pain, fever from combination therapy was shown over monotherapy and infection but less ototoxicity with the IP than the IV with PLD, topotecan, gemcitabine or paclitaxel. The com- route. However, the last IP study, GOG 252, failed to show bination of chemotherapy with bevacizumab significantly an advantage of IP over IV administration [22]. Thus, it is prolongs progression-free survival (PFS), however, only still not clear whether IP chemotherapy increases OS and patients with good performance status are eligible for this PFS. Additionally, the potential for catheter related compli- treatment. cations and toxicity must be considered. In certain cases of recurrent ovarian cancer, resection may be considered. It is eligible for patients who had a complete Treatment of recurrence remission and at least 12 months disease-free period after first-line treatment, and with a likelihood of successful radi- Despite the high response rate to primary treatment, major- cal surgery [14]. The Arbeitsgemeinschaft Gynaekologische ity of patients will develop recurrence [23]. Major option for Onkologie (AGO) Group DESKTOP OVAR I trial, based the treatment of recurrent ovarian cancer is chemotherapy. on retrospective analysis, showed three factors being inde- An important prognostic factor is the time from the end pendently associated with complete resection: macroscopi- of the previous treatment (treatment-free interval, TFI). The cally complete resection at first surgery, good performance 1 3 20 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 status, and the absence of ascites greater than 500 ml. These of chemotherapy. This therapy could also apply for the three factors were combined to the “AGO-score” that was patients with large residual disease after the primary sur- deemed positive if all three criteria were fulfilled. Survival gery and for those who have inoperable lesions. In the analysis showed median OS of 45.2 months in completely latter case, neoadjuvant chemotherapy is given, and the debulked patients, as compared with 19.7 months in patients patients, which will respond, qualify for the cytoreductive with incomplete resection (HR = 3.71; 95% 2.27–6.05; surgery combined with HIPEC. Another eligible group p < 0.0001) [27, 28]. AGO score was verified in a prospec- could include patients in whom laparoscopy revealed tive trial—AGO DESKTOP OVAR II (NCT00368420). malignancy, instead of apparently benign tumor. HIPEC The rate of complete resection was 76%, although negative is not recommended when the disease has disseminated to score might not exclude the possibility to achieve a com- the distant organs outside peritoneum [32]. plete resection. AGO DESKTOP OVAR III (ENGOT ov20/ HIPEC is criticized due to relatively high morbidity and NCT01166737) is randomized, phase III trial comparing mortality of the procedure. Major complications include second-line chemotherapy versus secondary cytoreduc- anastomotic leakage, bowel perforation, intraperitoneal tive surgery followed by chemotherapy, in patients with hemorrhage and wound dehiscence. Reported morbidity platinum-sensitive recurrent ovarian cancer with a positive rates range from 0 to 31.3% (Grade 3 and 4 morbidity AGO-score. OS data are not mature yet, but median PFS was according to the Clavien–Dindo classification) and mor - significantly improved in the experimental arm (14 months tality rates from 0 to 4.2%. Some authors argue that these without versus 20 months with surgery; HR = 0.66; 95% CI numbers are similar to those observed in patients undergo- 0.52–0.83; p < 0.001), even in those patients were complete ing cytoreductive surgery alone [33]. cytoreduction was not achieved [29]. In summary, DESK- So far, most of the results concerning HIPEC in ovar- TOP trials showed that it is possible to select patients who ian cancer are coming from phase I–II or retrospective might benefit from secondary cytoreductive surgery. studies, e.g., a case series analysis (246 ovarian cancer There are several recently completed and ongoing clini- patients with recurrent intraperitoneal lesions or with per- cal trials designed to evaluate new approaches for treatment sistent lesions after systemic treatment) showed that the for recurrent ovarian cancer, e.g. bevacizumab re-treatment median overall survival was 49 months after the maxi- (MITO16MANGO2b/NCT01802749; AGO-OVAR 2.21/ mum cytoreductive surgery and HIPEC [34, 35]. Several NCT01837251), PARPi in combinations with other biolog- randomized studies investigating HIPEC are currently ical drugs, as chemotherapy free option (ENGOT-OV24/ ongoing. A large randomized study (280 patients to be AVANOVA/NCT02354131; NRG004/NCT02446600; enrolled) conducted by the Netherlands Cancer Institute AGO-OVAR 2.28/ENGOT-ov28) [30], PARPi-based OVHIPEC (NCT00426257) and another smaller study options as maintenance therapy (SOLO 2/NCT01874353, CHORINE (NCT01628380) are investigating the benefit ICON 9 [31]), and immune checkpoint inhibitors (ATAL- of HIPEC after IDS for primary ovarian cancer. The larg- ANTE/NCT02891824; AGO-OVAR 2.29 [30]). est ongoing randomized study (444 patients to be enrolled) is the French CHIPOR study (NCT01376752), evaluating the efficacy of HIPEC in patients with platinum-sensitive Hyperthermic intraperitoneal chemotherapy recurrent disease. Two other randomized HIPEC trials (HIPEC) (NCT01539785 and NCT01767675) are also enrolling patients with recurrent disease, and another is investigat- Recently, a combination of cytoreductive surgery and hyper- ing the role of HIPEC after frontline cytoreductive sur- thermic intraperitoneal chemotherapy (HIPEC) is increas- gery (NCT01091636). Most interestingly, randomized ingly used for the management of peritoneal metastases. NCT02124421 trial is comparing the efficacy of cytore- This procedure is now accepted as a standard treatment for ductive surgery with HIPEC, and IV chemotherapy versus pseudomyxoma peritonei, peritoneal mesothelioma and the cytoreductive surgery and post-operative IP and IV chemo- peritoneal metastases from colorectal cancer. At some medi- therapy in primary ovarian cancer. cal centers, HIPEC is also used for the treatment of patients Before the results of these studies will be published, with ovarian cancer. and taking into account toxicity of HIPEC, at present, this In ovarian cancer patients, HIPEC is applied in com- technique cannot be recommended in daily practice. bination with systemic therapy which starts about three weeks after surgery. Cisplatin (optionally with doxoru- bicin) and taxanes are used most frequently for HIPEC. Best results are achieved in the treatment of platinum- sensitive tumors, although it is suggested that eligible are patients with late recurrences and after several lines 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 21 approved bevacizumab, in combination with paclitaxel, New therapeutic targets in ovarian cancer topotecan or pegylated liposomal doxorubicin (PLD) for therapy the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal Angiogenesis inhibitors cancer [37]. Phase III clinical trials investigating bevaci- zumab in ovarian cancer, those completed and still ongo- Angiogenesis is a tightly controlled dynamic process that ing are widely reviewed in [39, 40]. occurs primarily in embryo development, during wound GOG 218 was a double-blind, placebo-controlled, three- healing and in response to ovulation. However, it can be arm trial designed to determine whether the incorporation aberrantly activated during many pathological conditions of bevacizumab to standard chemiotherapy (cisplatin and such as cancer, diabetic retinopathy as well as numer- paclitaxel) in first-line treatment improves progression- ous ischaemic, inflammatory, infectious and immune free survival (PFS) in stage III and IV epithelial ovarian disorders. Among known regulators of angiogenesis are cancer patients who had undergone debulking surgery. The growth factors, matrix metalloproteinases, cytokines, and study evaluated bevacizumab added to standard chemo- integrins. A key player in the development of the patho- therapy followed by bevacizumab maintenance for 22 logical vascular network of tumor is Vascular Endothelial cycles (PFS 14.1 months) versus standard chemotherapy Growth Factor (VEGF) and its signaling pathway. It was (median PFS = 10.3  months). Patients in the third arm initially expected that blocking VEGF signaling in cancer received bevacizumab only with chemotherapy and did not will inhibit angiogenesis and cause tumor shrinkage, due have better clinical outcomes than those treated with stand- to the reduced blood supply. However, a variety of pre- ard chemotherapy alone (PFS = 11.2 months). Relative to clinical studies supported an alternative hypothesis that control group, the HR for progression of death was 0.908 anti-angiogenic agents can transiently ‘‘normalize’’ the (95% CI 0.795–1.040; p = 0.16) with bevacizumab-initiation abnormal structure and function of tumor vasculature to and 0.717 (95% CI 0.625–0.824; p < 0.001) with bevaci- make it more efficient for oxygen and drug delivery [36]. zumab throughout. The lack of a significant difference in In epithelial ovarian cancer, increased VEGF expression PFS between control group and the bevacizumab-initiation has a prognostic value: it is related with tumor grade, stage group implited that bevacizumab must be continued beyond of the disease, and patients’ survival. As VEGF receptors chemotherapy to delay disease progression [41, 42]. are present on the surface of ovarian cancer cells, it seems Another trial investigating the efficacy of standard that VEGF may play a unique role in the development chemotherapy with addition of bevacizumab in patients of this malignancy. By increasing vascular permeability with OFPC was the ICON7 study (NCT00483782). This within peritoneum, VEGF is also responsible for the for- phase III randomized, two-arm trial shown that the use of mation of ascitic fluid in ovarian cancer patients. Conse- bevacizumab given concurrently with 5 or 6 cycles of plat- quently, inhibition of pathological angiogenesis became inum-based chemotherapy and continued for an additional one of the new therapeutic options widely tested in ovarian 12 cycles improved PFS by about 2 months and increased cancer treatment; promising results are shown with beva- the response rate by 20%. The PFS and OS benefits were cizumab, cediranib and pazopanib, as well as aflibercept. much greater among the patients at high risk for progres- sion [improvements of 3.6 months (restricted mean) and 7.8 months (median) respectively], however, bevacizumab Inhibition of VEGF: bevacizumab did expand the range of toxic effects such as hyperthension and bowel perforation [43, 44]. Bevacizumab is a recombinant humanized monoclonal Thus, GOG-0218 and ICON7 trials showed that use of antibody against VEGF. It prevents VEGF from binding to bevacizumab maintenance after standard chemotherapy its receptor; it was shown that bevacizumab leads to nor- prolongs median PFS in patients with advanced epithelial malization of tumor vasculature and reduction of the inter- ovarian cancer [39]. The ongoing phase IV trial MITO16/ stitial tumor pressure, improving effectiveness of standard MANGO-2 (NCT01706120) is intended to explore the therapy. In 2004, it became the first clinically approved potential clinical factors and biological markers identifying angiogenesis inhibitor in the U.S. (approval for the treat- patients that will benefit most from addition of bevacizumab ment, in combination with standard chemotherapy, for to first-line chemotherapy, in terms of progression-free and colon cancer) [37]. In 2011, based on data from GOG0218 overall survival. Phase III BOOST trial (NCT01462890) is and ICON7 trials, bevacizumab has gained European Com- aimed on evaluation of optimal treatment duration of beva- mission approval for the first-line treatment together with cizumab combination with standard chemotherapy. standard chemotherapy in women with advanced OFPC Other studies suggest that the patients with recurrent [38]. In 2014, the Food and Drug Administration (FDA) ovarian cancer may benefit from bevacizumab, regardless 1 3 22 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 of the sensitivity to platinum treatment [45]. The first rand- of cancer [52]. The major survival factor for these cells is omized, open-label, phase III trial combining bevacizumab granulocyte–macrophage colony-stimulating factor 1 (GM- with standard chemotherapy in patients with recurrent plat- CSF1). A trial NCT02923739 is planned that will evaluate inum-resistant ovarian cancer who were given single-agent efficacy of emactuzumab, an inhibitor of GM-CSF recep- chemotherapy alone or with bevacizumab until the disease tor [53], following paclitaxel and bevacizumab, in recurrent progression was AURELIA (NCT00976911). Median PFS platinum-resistant OFPC. was 3.4 months with chemotherapy alone versus 6.7 months On the other hand, bevacizumab may induce hypoxia in with bevacizumab-containing therapy (HR = 0.48, 95% CI the tumor which may contribute to genomic instability, that 0.38–0.60; unstratified log-rank p < 0.001). Median OS was is thought to increase the sensitivity of cells to PARP inhibi- 3.3 months longer in the treatment group; however, it was tors [54]. not statistically significant. Safety analysis showed that The cost-effectiveness of bevacizumab was analyzed hypertension and proteinuria were more common in patients based on the results of ICON7 trial (NCT00483782), which treated with chemotherapy and bevacizumab than in the con- showed that adding bevacizumab (7.5 mg/kg) to standard trol group. Thus, this study showed that adding bevacizumab first-line chemotherapy improves not only PFS but also OS to chemotherapy significantly improved PFS and objective in a pre-specified group of women at high risk of progres- response rate (ORR); there was also trend toward longer sion (in a post hoc subset analysis of 465 high-risk patients, OS [46]. i.e., stage IIIC with residual disease > 1 cm or stage IV, the Another study with final results is OCEANS OS after standard chemotherapy was 28.8 months compared (NCT00434642), a randomized, placebo-controlled, phase with 36.6 months in the treatment group; HR = 0.64; 95% III trial, investigating the efficacy and safety of bevaci- CI 0.48–0.85; p = 0.002). There were three studies, one zumab maintenance after gemcitabine and carboplatin. The conducted from the perspective of the U.S. Medicare sys- patients with platinum-sensitive recurrent ovarian cancer tem [55], one according to the guidelines of U.K. National were treated with 6–10 cycles of chemotherapy and then Health Service [56] and one for Canadian public health care bevacizumab or placebo was continued until disease pro- system [57]. It was estimated that ovarian cancer patients at gression. Median PFS was 4 longer in the treatment group high risk of progression receiving bevacizumab plus stand- (HR = 0.484; 95% CI 0.388–0.605; log-rank p < 0.0001). ard chemotherapy experienced a mean incremental quality- Median OS was comparable between arms. No new safety adjusted life year (QALY) gain of 0.374 years. The incre- signals were identified following prolonged exposure to bev - mental cost-effectiveness ratio (ICER) of bevacizumab was acizumab, however, in experimental group adverse events approximately $167,771 per life-year saved (Medicare). In had greater frequency than in control group [47]. AGO- Canadian analysis, the ICER was $95,942 per QALY, while OVAR17 trial (NCT01462890) is intended to evaluate opti- in British study, it was £48,975, which was considered above mal treatment duration as maintenance. standard cost-effectiveness threshold (£20,000–£30,000 per Three phase III clinical trials of bevacizumab in recur- QALY) accepted by British National Institute for Health and rent ovarian cancer treatment (AURELIA, OCEANS and Care Excellence (NICE). GOG0213/NCT00565851) that investigated in total 1502 In conclusion, bevacizumab has been shown to improve patients, were included into two meta-analyses [48, 49]. PFS for 2–4 months and in some settings also OS, although Both meta-analyses showed that adding bevacizumab to it is associated with higher degree of side effects. A price standard chemotherapy improved ORR, PFS and OS, and it reduction would be required for this product to become cost- had a higher, but manageable incidence of toxicities (graded effective for majority of national health services. So far, 3–4). there were no predictive biomarkers found that could help to It was also tested whether adding bevacizumab to neoad- select patients, who could greater benefit from bevacizumab. juvant carboplatin-paclitaxel helps achieve complete resec- tion at IDS, in patients with advanced initially unresectable Inhibitors of VEGF receptors ovarian cancer (ATHALYA/NCT01739218). Complete resection rate was significantly higher in a group receiving Cediranib additional bevacizumab. The most common grade 3 adverse reactions to treatment occured in 62% of patients in the beva- Cediranib is anti-angiogenic multikinase inhibitor with cizumab group and 63% of patients in the control group. activity against all three VEGF receptors (VEGFR1-3). Post-operative complications occurred in 28 and 36% of the Several phase III trials with cediranib tested against differ - patients, respectively [50]. ent cancers have produced disappointing results; however, It was observed that bevacizumab can induce mac- promising activity has been seen with cediranib in ovar- rophage/monocyte infiltration [51] that has been identified ian cancer. ICON6 trial (NCT00532194) was a randomized as an independent poor prognostic factor in several types phase III double-blind, placebo-controlled study, which 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 23 enrolled women with platinum-sensitive relapsed ovarian PDGFRα/β, with lesser activity against RET, Flt-3 and cancer. It provided the evidence of activity and manage- Src. It has demonstrated significant anti-tumor activity in able toxicity of cediranib added to platinum-based chem- several tumor types in preclinical and clinical studies [63]. otherapy and continued as maintenance therapy for up to In 2014, FDA approved nintedanib for the treatment of 18 months. Median PFS of 11.0 months was observed in idiopatic pulmonary fibrosis. Nintedanib in combination the group treated with cediranib combined with chemo- with docetaxel was approved, in 2014, by the European therapy and then cediranib once-daily maintenance, while Commission for the treatment of adult patients with locally 8.7-month PFS was observed in the group receiving placebo advanced, metastatic or locally recurrent non-small cell during therapy and during maintenance (HR = 0.56; 95% CI lung cancer [64]. 0.44–0.72; p < 0.0001). In a group treated with cediranib in LUME-OVAR 1 (AGO-OVAR 12/NCT01015118) was a combination with chemotherapy then placebo maintenance, randomized, double blind, phase III trial where nintedanib median PFS was 9.9 months. Cediranib toxic effect was the was added to standard first-line chemotherapy, followed by most common cause for discontinuation: the most frequent nintedanib maintenance for a maximum of 120 weeks, in were diarrhea, neutropenia, hypertension, and voice changes patients with advanced epithelial ovarian cancer. This study [58, 59]. demonstrated significant improvement in median PFS in the In conclusion, addition of cediranib yielded an improve- treatment group compared with control group (17.2 versus ment in progression-free survival, albeit with added toxic 16.6 months; HR = 0.84; 95% CI 0.72–0.98; p = 0.0239). A effects. more pronounced PFS benefit was observed in a subgroup analysis in patients with < 1 cm residual tumor (21.1 versus Pazopanib 20.8 months; HR = 0.75; 95% CI 0.61–0.92; p = 0.005). The most common adverse events were gastrointestinal (diar- Pazopanib is a multikinase inhibitor of VEGFR1-3, plate- rhea) and hematological (neutropenia, thrombocytopenia, let-derived growth factor receptor α and β (PDGFRA and anemia). Drug-related adverse events leading to death PDGFRB) and c-Kit. A randomized phase II trial MITO-11 occured in three patients in the nintedanib group and in one (NCT01644825) was investigating the safety and efficacy patient in the placebo group [65]. of pazopanib in combination with paclitaxel in patients A randomized, placebo-controlled, phase II study with platinum-resistant ovarian cancer. PFS was signifi- NCT00710762 checked the maintenance treatment with nin- cantly longer in the experimental group (median PFS—6.35 tedanib following chemotherapy in patients with resistant or versus 3.49 months in placebo group; HR = 0.42; 95% CI partially platinum-sensitive relapsed ovarian cancer. It has 0.25–0.69; p = 0.0002). Adverse events included neutrope- shown a prolongation of PFS at 36 weeks compared with nia, fatigue, leucopenia, hypertension and anemia [60]. placebo (HR = 0.68; 95% CI 0.44–1.07; p = 0.07). There was A phase III study AGO-OVAR16 (NCT00866697) a higher rate of diarrhea, nausea, vomiting and hepatotoxic- designed to evaluate the efficacy and safety of pazopanib ity in the nintedanib group [66]. monotherapy versus placebo in women with OFPC who Nintedanib has shorter half-life (7–19  h) than beva- have not progressed after first-line chemotherapy, has cizumab (14–21  days). GINECO-OV119 (CHIVA/ shown better PFS in patients receiving pazopanib (median NCT01583322) was a randomized, double blind, placebo- PFS = 17.9  months) than in placebo group (median controlled phase II study of nintedanib in addition to neo- PFS = 12.3 months). HR for PFS was 0.77 (p = 0.0021). First adjuvant chemotherapy and IDS in patients with OFPC. No interim analysis of OS did not suggest any benefit. Grade 3 significant difference was observed between the placebo and or 4 adverse events of hypertension (30.8%), neutropenia the nintedanib group in terms of surgery duration as well as (9.9%), liver-related toxicity (9.4%), and diarrhea (8.2%) pre-operative and post-operative complications of the IDS were major side effects [61, 62]. [67]. In conclusion, pazopanib shows advantage toward longer There are currently ongoing phase II trials of nintedanib. PFS, both in the treatment of platinum-resistant/refractory METRO-BIBF (NCT01610869) is a randomized, placebo- ovarian cancer and in platinum-sensitive maintenance; how- controlled trial which primary objective is to explore the ever, further studies are necessary to identify subgroups of efficacy and safety of an all oral combination of nintedanib patients in whom improved efficacy may balance toxicity of and metronomic cyclophosphamide in patients with multi- that treatment. ply-relapsed advanced ovarian cancer, who have completed a minimum of two lines of previous chemotherapy and who Nintedanib for any reason are not suitable for further standard intrave- nous chemotherapy treatments [68]. Another ongoing phase Nintedanib (BIBF1120) is a next generation, potent triple II trial is NCT01669798 which main purpose is to see if nint- angiokinase inhibitor of VEGFR1/2/3, FGFR1/2/3 and edanib can increase the number of women with bevacizumab 1 3 24 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 resistant, persistent, or recurrent epithelial ovarian cancer phenomenon in which two genetic mutations are harmless who do not progress for at least 6 months [69]. when they occur separately, but can result in cell death when Nintedanib in combination with carboplatin and pacli- they arise in combination. The first clinical trials which vali- taxel is an active first-line treatment that significantly dated the clinical significance of this phenomenon involved increases PFS for women with advanced ovarian cancer, the study of PARPi in BRCA1 and BRCA2 (BRCA) muta- but is associated with more gastrointestinal adverse events. tion carriers with advanced solid tumors. In the BRCA wild- type cells, PARP and BRCA proteins participate in DNA Angiopoietin inhibitor repair via different pathways. In the presence of PARP inhi- bition, BRCA and other homologous recombination repair In addition to VEGF, other pathways involved in angiogen- pathway proteins carry out error-free DNA repair. In the esis are also exploited. Angiopoietin 1 and 2 (Ang1/2) bind BRCA-mutated cancer cell, inactivation of both alleles of to Tie-2 receptor, what results in stimulation of endothelial either BRCA1 or BRCA2 leads to homologous recombina- cells proliferation, motility and survival. Trebananib (AMG- tion deficiency (HRD). Treating such cells with a PARPi 386) is a fusion protein that selectively binds Ang1/2, pre- leads to massive DNA damage and cellular lethality (rev. venting signaling through Tie-2. The available results from in: [72]). Also, other tumor-specific homologous recombi - two clinical trials: NCT00479817 [70] and TRINOVA-1 nation defects may be potentially exploited, such as somatic (NCT01204749) [71] were included in meta-analysis [49] BRCA mutations, mutations in ATM, ATR, RAD51, and that showed prolonged PFS (HR = 0.67; 95% CI 0.58–0.77; others [73, 74]. First PARP inhibitor approved for clinical p < 0.00001) and OS (HR = 0.81, 95% CI 0.67–0.99, use was olaparib [75]. p = 0.04) for trebananib in combination with weekly pacli- Multiple trials were designed to evaluate PARP inhibi- taxel in women with recurrent, partially platinum-sensitive tors in ovarian cancer: (1) in a first-line treatment (SOLO1/ or -resistant OFPC. NCT01844986, NCT02470585, PRIMA/NCT02655016, PAOLA1/ NCT02477644, NEO/NCT02489006), (2) in Summary of anti‑angiogenic therapies the treatment of platinum-sensitive relapse (ENGOT- OV24/AVANOVA/NCT02354131, NCI-OVM1403/ Several anti-angiogenic therapies have been shown effective NCT02446600, SOLO3/ NCT02282020, ARIEL4/ in improving PFS of recurrent ovarian cancer with a poten- NCT02855944), (3) in maintenance after chemotherapy tial benet fi of 2–6 months, although with added toxic effects. in platinum-sensitive disease (ENGOT-OV16 NOVA/ Anti-angiogenic drugs are given to unselected patients as NCT01847274, SOLO 2/NCT01874353, ARIEL3/ no predictive markers were found so far. Some data indicate NCT01968213) or (4) in the treatment for platinum-resistant that patients whose tumor blood perfusion or oxygenation disease, and (5) in combination with immune checkpoint increases after the initiation of anti-angiogenic therapy, inhibitors and other biological drugs (widely reviewed in: survive longer than those whose tumor perfusion does not [54, 76–78]). change or decreases [36]. This indicates the directions for further studies. Importantly, when several anti-angiogenic Olaparib therapies (bevacizumab, VEGFR inhibitors and trebananib) were analyzed in two subgroups of (1) platinum-resistant Olaparib (AZD2281) obtained in 2014 an accelerated and (2) platinum-sensitive recurrent ovarian cancer, it was approval by FDA for the treatment for advanced ovarian shown that the PFS improved significantly in both groups, cancer in patients with known or suspected germline BRCA while the OS was clearly better in the platinum-sensitive mutation, who have been treated with three or more prior group, but insignificant in the platinum-resistant group lines of chemotherapy [75]. In the same year, European [49]. These data suggest that it could be possible to improve Medicine Agency (EMA) authorized olaparib as monother- survival with a more personalized use of anti-angiogenic apy in maintenance treatment of patients with platinum sen- agents. sitive, relapsed BRCA-mutated (germline or somatic) high- grade serous epithelial ovarian cancer who are in complete response (CR) or partial response (PR) following platinum- PARP inhibitors based chemotherapy. The approval of olaparib was based on data from Study The Poly(ADP-ribose) Polymerase (PARP) proteins are a 19 (AZ19/NCT00753545), a phase II clinical trial that eval- family of 17 enzymes involved in a wide range of cellular uated its efficacy and safety, compared with placebo, in plat- functions, of which PARP1 and PARP2 are known to be inum-sensitive relapsed high-grade serous ovarian cancer engaged in DNA repair. Cancer treatment with PARP inhibi- patients [79]. The study showed that olaparib maintenance tors (PARPi) exploits the concept of synthetic lethality, a therapy significantly prolonged progression-free survival, 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 25 compared with placebo, in patients with BRCA-mutated phase III trial in patients with germline BRCA-mutated, ovarian cancer (median PFS 11.2 versus 4.3  months; recurrent OC who failed two or more lines of chemother- HR = 0.18; 95% CI 0.10–0.31; p < 0.0001). Adverse events apy, in which olaparib will be compared with single-agent related to olaparib were mostly of grade 1 to 2 and included chemotherapy. nausea, fatigue, vomiting, taste alteration and anorexia, Combined treatment options with a number of other although grade ≥ 3 adverse events were most frequent in the agents are also being assessed. Olaparib was studied in olaparib group (40%) than in the placebo group (22%). The combination with the anti-angiogenic multikinase inhibi- most pronounced were nausea (2 versus 0%), fatigue (7 ver- tor, cediranib. Median PFS was 17.7 months for women sus 3%), anemia (5 versus 1%), neutropenia (4 versus 1%). treated with cediranib and olaparib (n = 44) compared with In several other trials, olaparib was tested as maintenance 9.0 months for those treated with olaparib alone (n = 46; therapy alone or in addition to standard chemotherapy, as HR = 0.42; p = 0.005) [81, 83]. OS data were not mature; prior- and post-surgery treatment, and in combination with however, there was a trend toward longer OS in the combi- different new drugs. The SOLO1 study (NCT01844986), nation group. Treatment-related adverse effects were more conducted in collaboration with the Gynecologic Oncology common in patients treated with cediranib plus olaparib than Group (GOG), was designed to assess the role of mainte- with monotherapy. nance olaparib after frontline chemotherapy for OC patients Recently, results of phase I studies of olaparib in combi- with germline BRCA mutations. SOLO2, performed in col- nation with the PI3K inhibitor BKM120 (NCT01623349) laboration with the European Network of Gynaecological [84] and the AKT inhibitor AZD5363 (NCT02208375) [85] Oncological Trial (ENGOT) Groups, was investigating have been reported with evidence of activity in OC. the role of maintenance olaparib after two or more lines of chemotherapy for OC patients with germline BRCA muta- Niraparib tions. Both trials are randomized, double-blind, placebo- controlled. The primary endpoint was investigator-assessed Niraparib (MK4827) is an oral, selective PARP-1 and -2 PFS which median was 19.1 months in the treatment group inhibitor that was shown in preclinical studies to induce syn- versus 5.5 months in the placebo group (HR 0.30; 95% CI thetic lethality in tumors with loss of PTEN and BRCA1 or 0.22–0.41; p < 0.0001). The results of blinded independ- BRCA2 function [77]. Clinical studies showed that niraparib ent central review of SOLO2 study were shown in March significantly improved PFS in patients with platinum-sensi- 2017 at the Society of Gynecologic Oncology Annual Meet- tive recurrent ovarian cancer, regardless of BRCA mutation ing on Women’s Cancer, indicating significantly longer PFS or HRD status, although its efficacy was highest in patients (30.2 months with olaparib versus 5.5 months with placebo; with BRCA mutations. HR = 0.25 (95% 0.18–0.35), p < 0.0001) [80]. Based on In the end of April 2017, niraparib obtained FDA approval these data the FDA has granted a priority review to a new for the maintenance treatment of patients with recurrent OC application for olaparib as a maintenance therapy in relapsed who are in a CR or PR to platinum-based chemotherapy patients with platinum-sensitive ovarian cancer. [86]. Approval was based upon data from the international Pooled data from six olaparib trials (two phase I trials and phase III ENGOT-OV16/NOVA (NCT01847274) trial, a four phase II studies) that recruited women with relapsed double-blind, placebo-controlled study that enrolled 553 disease were used to explore the activity of olaparib in rela- patients. Approximately two thirds of study participants tion to the number of prior treatment lines in patients with did not have germline BRCA mutations. PFS in a group germline BRCA- mutated ovarian cancer. In the pooled pop- with germline BRCA mutations was 21.0 months, while in ulation of 273 patients who had been administered three or the placebo group—5.5 months (p < 0.0001). In the group more lines of prior chemotherapy, the objective response with non-mutated BRCA but with HRD positive score, rate (ORR) was 36% with a 7.4 month median duration [81]. PFS was 12.9 months while in placebo group—3.8 months Olaparib is also under investigation in combination with (p < 0.0001). Even in a group without mutations and HRD- chemotherapy. In a randomized, open-label, phase II study negative, PFS was longer in niraparib-treated patients (6.0 (NCT01081951), patients with platinum-sensitive, recurrent versus 3.9 months, p = 0.02). Niraparib reduced the risk OC received either olaparib with paclitaxel and carboplatin, of progression or death by 74% in patients with germline followed by olaparib maintenance, or paclitaxel and carbo- BRCA mutations (HR = 0.26) and by 55% in patients with- platin without any maintenance treatment. PFS was slightly out mutations (HR = 0.45). The most common grade 3/4 but significantly improved for the olaparib group versus adverse reactions to niraparib in the NOVA trial included chemotherapy alone (12.2 versus 9.6 months; HR = 0.51, thrombocytopenia (29%), anemia (25%), neutropenia (20%), 95% CI 0.34–0.77; p = 0.0012), particularly in patients with and hypertension (9%). The majority of hematologic adverse BRCA mutations (HR = 0.21, 95% CI 0.08–0.55; p = 0.0015) events were successfully managed via dose modification [82]. SOLO3 (NCT02282020) is an ongoing randomized, [87]. 1 3 26 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 The ongoing development program for niraparib includes BRCA mutation, BRCA-wild type/LOH-high, BRCA- a Phase III trial in patients who have received first-line treat- wild type/LOH-low and BRCA-wild type/LOH indetermi- ment for ovarian cancer (PRIMA/NCT02655016) and a nate) was 10.8 months (HR = 0.37, p < 0.0001), while in registrational Phase II trial in patients who have received the placebo group median PFS was 5.4 months. The most multiple lines of treatment for ovarian cancer (QUADRA/ common grade 3 or higher adverse reactions to rucaparib NCT02354586). Several combination studies are also in the ARIEL3 trial included anemia (18.8 versus 0.5% underway, including trials of niraparib plus pembrolizumab in the placebo group) and elevated alanine/aspartate ami- (TOPACIO/NCT02657889) and niraparib plus bevacizumab notransferase (10.5 versus 0%) [91]. In the ongoing ARIEL4 (ENGOT-OV24/AVANOVA/NCT02354131). (NCT02855944) confirmatory study, the primary purpose is to assess the efficacy and safety of rucaparib versus standard Rucaparib chemotherapy in the treatment for relapsed ovarian cancer in patients with BRCA mutation. Rucaparib (CO338, AGO14699, PF01367338) is an orally administered, small molecule-based PARP-1, -2 and - 3 Other PARP inhibitors inhibitor. In December 2016, the FDA granted an acceler- ated approval for rucaparib as monotherapy for the treatment There are several other PARPi currently tested for the of patients with advanced ovarian cancer associated with treatment for different cancers, including ovarian. Veli- BRCA mutations (germline and/or somatic) who have been parib (ABT888) is an orally administered inhibitor of both treated with two or more lines of chemotherapy [88, 89]. PARP-1 and - 2 that is extensively studied (currently there ARIEL2 (NCT01891344) was a phase II biomarker are 26 registered trials concerning ovarian cancer), in com- study that assessed if loss of heterozygosity (LOH) level, bination with chemotherapy, and as a single agent (rev in: can predict response to rucaparib. ARIEL2 enrolled patients [77]). with platinum-sensitive, recurrent, high-grade serous or Talazoparib (BMN673) has been very promising in pre- endometrioid ovarian cancer after one or more lines of clinical studies, but it is currently tested mostly in the phase platinum-based chemotherapy and whose last treatment I trials. Phase II trial (NCT 02326844) which tested tala- was platinum-based. The primary objective was to evaluate zoparib as monotherapy for patients with BRCA-mutated clinical activity of rucaparib in three subgroups, delineated ovarian cancer who had prior PARPi treatment has been by BRCA mutation and HRD status (expressed by LOH terminated. level, quantified with a next-generation sequencing assay): (1) BRCA-mutated, (2) BRCA-wild type/LOH-high and (3) Summary of PARP inhibitors BRCA-wild type/LOH-low. Median PFS after rucaparib treatment in a group with BRCA mutations was 12.8 months PARPi (olaparib, niraparib) have recently become a standard (9.0–14.7), in the LOH high group was 5.7 months (5.3–7.6), of care for patients with recurrent BRCA-mutated ovarian and in the LOH low group was 5.2 months (3.6–5.5). PFS cancer. In addition, it was shown that olaparib significantly was significantly longer in the BRCA mutant and LOH high improved PFS in patients with platinum-sensitive recurrent groups compared with the LOH low group. These results ovarian cancer, regardless of BRCA mutation. Niraparib suggested that assessment of tumor LOH can be used to showed improved PFS in the same setting, regardless of identify patients with BRCA wild-type platinum-sensitive BRCA mutation and HRD status. It suggests that although ovarian cancers who might benefit from rucaparib. efficacy of both agents is highest in BRCA-mutated popula - The most common grade 3 adverse reactions to rucaparib tion, other patients may benefit, too. Other settings are cur - in the ARIEL2 trial included anemia or low hemoglobin rently extensively tested, e.g., PARPi in primary treatment (22%), elevated alanine aminotransferase or aspartate ami- and in maintenance after primary treatment, PARPi as mon- notransferase (12%), small intestine obstruction (5%), malig- otherapy or combined with chemotherapy and/or with other nant neoplasm progression (5%) [90, 91]. biological agents. However, the utility of PARPi in combina- Rucaparib was also tested as maintenance treatment for tion with chemotherapy is concerned with enhanced toxic- platinum-sensitive patients, stratified into three groups in ity, thus more promising are strategies combining PARPi the ARIEL3, a double-blind, placebo-controlled, phase III with anti-angiogenic agents, or with inhibitors of the P13K/ trial that enrolled 564 women (NCT01968213). PFS after AKT pathway and new generation of immunotherapy (rev. rucaparib treatment in a group with BRCA mutations was in: [92]). 16.6  months (HR = 0.23, p < 0.0001), in the HRD-group As only BRCA1 or BRCA2 mutations and cisplatin (including patients with BRCA mutation or BRCA wild sensitivity are accepted predictors of a response to PARPi. type/LOH-high) was 13.6 months (HR = 0.32, p < 0.0001), Thus, it is now widely accepted that BRCA testing should and in the “intent to treat” group (including patients with be offered for all women with ovarian cancer. 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 27 Exact characteristics of long-term responders is still to may form homodimers or may cooperate by forming het- be recognized and a better HRD test is needed [93]. Astra erodimers, both types of interactions resulting in an active Zeneca AZ HRR test examines mutations in 15 genes related signaling trough Ras-Raf-MAPK and PI3K/AKT pathways, with homologous repair (BRCA1/2, ATM, RAD51B/C/D, what leads to the increased cell proliferation and inhibition RAD54L, FANCJ, FANCL, FANCN, BARD1, CHEK1/2, of apoptosis. Thus, ErbB proteins are potential therapeutic CDK12, PPP2R2A). However, many of these mutations are targets in many cancers. of low frequency and some confer only very slight sensitiv- In ovarian cancer, high EGFR expression was shown to ity to PARPi. Myriad MyChoice test is based on the assess- be related with shorter disease-free survival (DFS) and OS. ment of three independent indicators of genome instabil- Unfortunately, none of EGFR inhibitors (erlotinib, cetuxi- ity: telomeric allelic imbalance, large-scale transitions, and mab or lapatinib) showed promising results in clinical trials LOH. Assay is based on whole genome profiling of single investigating its efficacy in ovarian cancer treatment. Disap- nucleotide polymorphisms (SNPs) [51, 94]. pointing results were also achieved with pertuzumab which Although current data indicate that PARPi are well toler- is directed against HER2. ated, careful assessment of moderate and late-onset toxicities is required, as these drugs are intended to be taken for a long periods of time. Folate receptor α inhibitors Clinical studies suggest that PARPi may have a greater impact on prolonging PFS in BRCA-mutated patients then Folate receptor alpha (FRα) is glycosylphosphatidylinositol anti-angiogenic therapy. In addition, PARPi are better toler- protein, anchored in the cell membrane. In physiological ated, and have a benefit of oral administration. However, conditions, it is present only in some polarized epithelia cost-effectiveness of this therapy is currently challenging; and its expression is strictly confined to the apical/luminal e.g., according to the appraisal by NICE, the ICER for cell surface. It is, however, frequently overexpressed in the olaparib maintenance in platinum-sensitive relapsed ovarian tumors of epithelial origin, where it loses its polarized loca- cancer versus routine surveillance is likely to be more than tion and is present on the entire cell surface. Thus, FRα is a £92,000 per QALY gained [90]. It was also suggested by potential biomarker for cancer cells detection and a promis- these authors that with limited health care resources, future ing therapeutic target (rev. in: [97]). clinical trials should incorporate a prospective collection of Folates play an essential role in the biosynthesis of costs, long-term treatment toxicity, and quality of life. purines and thymidine, which are required for DNA synthe- Cost-effectiveness analysis of olaparib and rucaparib was sis, methylation and repair. The majority of folate transport recently presented on American Society of Clinical Oncol- is mediated by low affinity solute transporters, while the ogy 2017 Annual Meeting. Platinum-based combinations proteins from FR family assure high affinity transport. Thus, were found the most cost-effective at $1672/PFS month, targeting FRα does not block completely folate intake and as compared to non-platinum agents ($6688/month), bev- this is not a major mechanism responsible for anti-cancer acizumab-containing regimens ($12,482/month), olaparib activity of this approach, which is rather related with anti- ($13,3731/month), and rucaparib ($14,034/month). Consid- body-dependent cellular cytotoxicity [98]. ering a cost of $114,478 for olaparib and $137,068 for ruca- Ovarian cancer is probably the tumor in which FRα is parib prior to progression, costs associated with PARPi were most frequently overexpressed. It is estimated that over 80% 7.1–8.3 times higher than platinum combinations [95, 96]. of serous ovarian cancers show FRα expression Lutz [99]. In The authors of this report commented that “while the data on addition, expression level of FRα has been also correlated the PARP inhibitors is promising, the unfortunate nature of with tumor stage and higher histological grade, with poor new therapies is their inherent associated high costs reflect- response to chemotherapy, and worse survival. Moreover, ing the high costs of development”. FRα expression is not affected by chemotherapy itself (rev. in: [97, 100]). FR expression can be exploited therapeutically by sev- EGFR tyrosine kinases inhibitors eral strategies, e.g., using specific antibodies or antibody- like binders to target FRα itself. An example is farletu- ErbB family consists of four closely structurally and func- zumab, which is currently tested in several clinical trials. tionally related tyrosine kinases: the Epidermal Growth Other possibility is to use an antibody-drug conjugates to Factor Receptor (EGFR/HER1/ErbB1), Human Epidermal deliver a drug of choice into cancer cell. IMGN853 (mir- Growth Factor Receptor 2 (HER2/neu/ErbB2), HER3/ErbB3 vetuximab soravtansine) is a representative, currently and HER4/ErbB4. The main ligand of ErbB1 (EGFR) is Epi- entering into clinical trials. However, most extensively dermal Growth Factor (EGF). ErbB2 has no known ligands, evaluated are folate–drug conjugates which have been while ErbB3 has no active kinase domain. ErbB receptors used in several preclinical studies to deliver toxic proteins, 1 3 28 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 radiopharmaceuticals, antisense oligonucleotides, chemo- help to define a subgroups of patients that will benefit from therapeutic agents and their liposomal formulations, to the this treatment. cancer cells [rev. in: [99]]. A conjugate which is currently tested in clinical trials is vintafolide. Vintafolide FRα targeting may be also useful for imaging purposes: a small molecule targeting FRα conjugated with technetium- Vintafolide (MK-8109, EC145) is a water-soluble folate 99m-based imaging agent (99mTc-etarfolatide, FolateScan) conjugated with microtubule destabilizing agent, a vinca is tested (NCT03011320) for identification of cells express- alkaloid derivative, desacetylvin-blastinemonohydrazide ing FRα [97]. (DAVLBH). DAVLBH disrupts the formation of the mitotic In addition, anti-FRα vaccines (NCT02111941; spindle, which leads to cell cycle arrest and cell death. NCT02764333) and FRα-targeting T cell therapies are Folate–drug conjugate binds to FRα and enters the cell via exploited (rev. in: [98, 100]). endocytosis [99]. Early clinical evidence suggested that vin- tafolide may have anti-tumor effect in women with advanced ovarian cancer [104]. Open-label phase II PRECEDENT Farletuzumab trial (NCT00722592) evaluated the effects of adding vinta- folide to PLD in patients with platinum-resistant recurrent Farletuzumab (MORAb-003) is a humanized monoclonal ovarian cancer. Median PFS was 5.0 months in experimental antibody with high affinity for FRα [99]. Preclinical stud- group versus 2.7 months for PLD alone. The study showed ies suggest that farletuzumab exerts its anti-tumor activ- that FRα-positive patients (based on etarfolatide imaging) ity through different mechanisms, either by promotion of benefited from vintafolide and PLD combination therapy, tumor cell lysis by antibody-dependent cellular cytotoxicity whereas patients with FRα-negative tumors did not [103]. or complement-dependent cytotoxicity. Other mechanisms Unfortunately, phase III PRECEDENT trial (NCT01170650) are based on induction of sustained autophagy, resulting in has been discontinued because the experimental arm did not a decreased proliferation, or inhibition of the interaction meet the pre-specified primary outcome for PFS improve- between FRα and lyn kinase, leading to reduced intracellu- ment [105]. lar growth signaling [101]. Phase I/II clinical trials demon- strated feasibility and safety of farletuzumab; the most com- Mirvetuximab soravtansine (IMGN853) mon adverse events were hypersensitivity reactions, fatigue and diarrhea. A phase II trial (NCT00318370) showed that IMGN853 belongs to the class of antibody-drug con- farletuzumab with carboplatin and taxane may enhance the jugates; it consists of an anti-FRα antibody coupled to a response rate and duration of response in platinum-sensitive highly potent cytotoxic maytansinoid payload. It is currently ovarian cancer patients with first relapse after remission of tested in three phase I trials (NCT02996825, NCT01609556, 6–18 months [102]. Unfortunately, the efficacy data in phase NCT02606305) and one phase III trial (NCT02631876), III trials are conflicting [103]. One phase III randomized, which is an open-label, randomized study designed to com- placebo-controlled trial (NCT00738699) was designed pare the safety and efficacy of IMGN853 to single-agent investigate farletuzumab in combination with weekly pacli- chemotherapy in women with platinum-resistant FRα- taxel in patients with platinum-resistant recurrent or refrac- positive advanced EFPC. tory EOC. This study was terminated because interim analy- sis showed that it was unlikely to meet primary endpoint of two-year PFS. Immunotherapy for ovarian cancer Another phase III randomized, double-blind, placebo- controlled trial (NCT00849667) was aimed to compare the Cancer immunotherapy includes different approaches aimed efficacy and safety of six cycles of carboplatin and taxane to enhance an individual’s own immune system to elimi- with and without weekly farletuzumab in patients with a nate tumor cells. EOC is an immunogenic tumor that can first platinum-sensitive relapse of EOC. No significant dif- be recognized by the host immune system; tumor reactive ferences in PFS among the treatment arms were observed. T cells and antibodies can be detected in the blood, tumor However, post hoc exploratory analysis revealed a trend and ascites of EOC patients with advanced disease (rev. in: toward improved PFS in some patient subsets [101]. It is [106]). It was also shown that higher tumor infiltration with suggested that lack of improvement in PFS in the above stud- CD8 + T cells (tumor-infiltrating lymphocytes—TILs) is ies was due to the fact that patients were recruited without positively correlated with patients survival [107, 108]. analyzing FRα expression level. On the other side, useful- Several approaches were designed for either enhancing ness of FRα as a predictive biomarker is unclear. Thus, fur- unspecific immune response or inducing specific adaptive ther studies are necessary to identify biomarkers that will response against tumor antigens, including passive or active 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 29 immunotherapy (widely reviewed, e.g., in: [109–111]). combined with WT1 analog peptide vaccine plus mon- Unfortunately, although some of the studies reported a tanide (an incomplete Freund’s adjuvant), and GM- positive outcome from the treatment of ovarian cancer with CSF (a potent stimulator of dendritic cell maturation) specific immunotherapy, these results were not significant in (phase I, NCT02737787). Nivolumab is also investi- meta-analysis by Alipour et al. 2016 [112]. More promising gated in combination with oregovomab (anti-CA125 seem to be newer approaches involving immune checkpoint antibody) in phase I/II study (NCT03100006); with inhibitors, alone or in combination with other biological bevacizumab (phase II, NCT02873962); or ipilimumab therapies and drugs [110]. (NCT02498600, NCT02834013, NCT02923934) and in combination with epacadostat (an inhibitor of indoleam- Checkpoint inhibitors and immune modulators ine 2,3-dioxygenase; IDO1) (phase I/II, ECHO-204/ NCT02327078). In physiological conditions, distinct immune checkpoint – Ipilimumab is a recombinant, human monoclonal proteins either stimulate or block T lymphocyte activity, to antibody targeting CTLA-4 that is FDA-approved for regulate the balance between immune response and toler- the treatment for melanoma. It is tested in monother- ance. Checkpoint receptors such as Cytotoxic T Lympho- apy for recurrent platinum-sensitive ovarian cancer cyte Associated Protein 4 (CTLA-4) and Programmed Cell (NCT01611558) and in combination with nivolumab Death Protein 1 (PD-1) act to reduce autoimmune responses (see above). against self-tissues. In cancer patients their activity is often – Avelumab is a humanized monoclonal anti-PD-L1 anti- increased, what results in the impaired natural anti-cancer body that does not block PD-1 interaction with PD-L2. immunity. The rationale behind using immune-checkpoint In March 2017, it was FDA approved for the treatment inhibitors is to unblock anti-tumor responses. Alternatively, of Merkel cell skin carcinoma. It is currently tested in activating stimulatory molecules, may be implemented to two Phase III trials for ovarian cancer: one for first-line enhance pre-existing anti-cancer immune responses [109, therapy in combination with carboplatin and paclitaxel 113, 114]. (Javelin ovarian 100/NCT02718417) and the other for the Two factors were recognized, so far, that help predict treatment for recurrent platinum-resistant/refractory dis- tumor response to immune checkpoint inhibitors, namely ease, in combination with PLD versus PLD alone (Javelin accessibility of the tumor by effector immune cells and reli - ovarian 200/NCT02580058) ance of tumor cells on immune checkpoint pathways. The – Atezolizumab is a humanized, monoclonal antibody tar- surrogate markers for these features are, e.g., the presence geting PD-L1 that is FDA-approved for the treatment of of TILs in the tumor and PD-1 ligand (PD-L1) expression, bladder/urothelial carcinomas. It is tested in several trials respectively. Based on these markers, it is estimated that for recurrent ovarian cancer, e.g., phase III randomized, over a half of high-grade serous ovarian cancers represents double-blinded trial ATALANTE (NCT02891824) that a pattern of adaptive immune resistance and is likely to is aimed to evaluate atezolizumab versus placebo in respond to immune checkpoint inhibitors, while in other his- combination with platinum-based chemotherapy and tological types such phenotype is less frequent (about 25% of bevacizumab. Phase II randomized trial (EORTC-1508/ clear cell and mucinous cancers) or absent (low-grade SOC) NCT02659384) is intended to investigate atezolizumab [Gaillard et al. 2016]. with bevacizumab or acetylsalicylic acid in patients with Currently, several immune checkpoint inhibitors are in recurrent platinum-resistant ovarian cancer. Phase II/III early phase testing for ovarian cancer treatment (phase I and randomized study (NCT02839707) is evaluating safety II) (rev in: [110, 113]). and efficacy of PLD with atezolizumab and/or bevaci- zumab. – Pembrolizumab is an anti-PD-1 antibody, FDA-approved – Durvalumab (MEDI4736) is a monoclonal antibody for the treatment for melanoma and NSCLC. Currently, it against PD-L1. It is currently evaluated in phase I/II is tested as monotherapy (NCT02608684, NCT02440425, study (NCT02484404) in combination with olaparib NCT02537444, Keynote-100/NCT02674061) or in com- and cediranib in advanced or recurrent ovarian cancer; bination with PLD (NCT02865811) or with bevacizumab in phase I/II study (NCT02431559) in combination and cyclophosphamide (NCT02853318) in patients with with PLD and motolimod (a Toll-like receptor 8 ago- recurrent ovarian cancer. Pembrolizumab is also evalu- nist), in recurrent platinum-resistant ovarian cancer; in ated in combination with carboplatin and paclitaxel as a phase I study (NCT01975831) in combinantion with first-line chemotherapy (NCT02520154, NCT02766582); tremelimumab (a human monoclonal antibody against – Nivolumab is an anti-PD-1 antibody, FDA approved CTLA-4); and in combination with azacitidine (phase I for the treatment for melanoma. It is currently tested study METADUR/ NCT02811497) in platinum-resistant in patients with advanced cancers, including OFPC, ovarian cancer. Durvalumab is also tested in combination 1 3 30 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 with TPIV200/huFR-1 (a multi-epitope anti-folate recep- fragments of diphtheria toxin and human interleukin-2 were tor vaccine), in patients with platinum-resistant ovarian tested in already completed study NCT00703105, but no cancer (phase II study, NCT02764333). Another phase I/ results were published so far. CVac, a MUC1-targeted DC II study (NCT02726997) is aimed to evaluate pharmaco- vaccine, was tested in CAN-003/NCT01068509 study. A dynamics and feasibility of durvalumab in combination variable CVac-derived, mucin 1-specific T cell response with chemotherapy for the first-line treatment of ovarian was measured. PFS was not significantly longer in the treat- cancer. ment group, but one subgroup (patients in second remission) showed an improved PFS and OS [118]. Another study on So far, preliminary clinical data show limited efficacy CVac (NCT01617629) was completed, but no results were of these agents in ovarian cancer with objective response published, so far. rates of 10–15% and with some durable responses. Thus, it Other trials include phase I study (NCT01376505) remains to be established, why some patients do not respond on a vaccine composed of two HER2 peptides: MVF- to immune checkpoint inhibitors and to find predictive bio- HER-2(597–626) and MVF-HER-2 (266–296) tested in markers. Another task is to determine the best combination different metastatic tumors, including OC; a study on therapy [113]. ID-LV305 vaccine, consisting of lentiviral vector targeting DCs, and containing sequences encoding the NY-ESO-1 Therapeutic vaccines antigen (NCT02122861); a NCT02387125 trial on CMB305, a combination product composed of a cancer vaccine con- Therapeutic cancer vaccines are intended to induce cell- taining an NY-ESO-1 antigen (LV305) and glucopyranosyl mediated immunity, so that immune cells are activated to adjuvant in lipid emulsion (G305). A mixed bacteria vaccine identify and eliminate malignant cells. For this purpose, (MBV/Coley’s toxin) was tested as non-specific immuno- selected tumor-associated antigens are delivered using dif- therapy in patients with different tumors expressing NY- ferent approaches; there are cell-based vaccines, peptide/pro- ESO-1 antigen in phase I study (NCT00623831). Ten of tein, epigenetic, and genetic vaccines tested against different 12 patients showed a consistent increase in serum IL-6 lev- tumors, which are either given alone or in combination with els and body temperature. A subgroup of patients showed different adjuvants, such as cytokines or other stimulatory increasing levels of TNF-α, IFN-γ, and IL1-β [119]. The factors (reviewed in: [106, 115, 116]). MVA-5T4 vaccine (a recombinant modified vaccinia Ankara In ovarian cancer, there are several tumor-associated anti- viral vector encoding the 5T4 fetal oncoprotein) is tested in gen molecules found on the surface or inside the cells that TRIOC/NCT01556841 trial. A phase II/III trial (MIMOSA/ can potentially serve as targets for immune recognition and NCT00418574) on abagovomab (a murine anti-idiotypic response; these are, e.g., CA125, p53 protein, FRα, HER2, antibody against CA-125) in maintenance therapy was ter- and cancer–testis antigens, like MAGE-A4 and NY-ESO-1 minated, as no benefit on primary end point (recurrence-free [117]. Currently, there are mainly pilot and phase I or II survival) was observed [120]. trials on the use of therapeutic vaccines in ovarian cancer (widely reviewed in: [106]). For patients with OFPC there are ongoing studies on p53- Adoptive T cell transfer MVA vaccine, based on modified vaccinia virus expressing p53 protein (NCT02275039); on an autologous oxidized A third major trend of immunotherapy for ovarian cancer tumor cell lysate vaccine given with montanide and Poly- is adoptive T cell transfer. This therapy uses autologous or ICLC (a Toll-like receptor 3 stimulant) (NCT02452775); allogeneic anti-tumor lymphocytes to induce cancer regres- on gemogenovatucel-T vaccine that consists of autologous sion. In this approach, peripheral blood lymphocytes (PBLs) tumor cells electroporated with FANG vector encoding GM- are isolated via apheresis, than tumor-specific lymphocytes CSF, and a bi-shRNA targeting furin convertase, thereby are selected and expanded in vitro, then re-introduced into downregulating endogenous immunosuppressive TGF-β1 the patient. Alternatively, PBLs can be genetically modified and β2 (VITAL/NCT02346747); and on IDO1 inhibitor to enhance their anti-tumor activity (rev. in: [109, 121]). INCB024360, in combination with CDX-1401 (a fusion pro- Several phase I and II trials of adoptive T cell transfer tein, consisting of NY-ESO-1 antigen and a human mono- are currently underway for patients with advanced cancers, clonal antibody against the endocytic dendritic cell receptor, including ovarian, e.g., treatment with NY-ESO-1 antigene- DEC-205) and Poly-ICLC (NCT02166905). reactive TCR (retroviral vector transduced) autologous PBLs In ovarian cancer, the tumor-specific intra-nodal autol- alone (NCT01567891), or with NY-ESO antigene-pulsed ogous alpha-DC1 vaccines are tested in phase I/II study dendritic cells as a vaccine (NCT01697527). Other ongo- NCT02432378. A dendritic cell (DC) vaccine and ontak ing phase I/II trials are investigating anti-MAGE-A3 anti- (denileukin diftitox), a cytotoxic fusion protein containing gene-reactive TCR (retroviral transduced) autologous PBLs 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 31 (NCT02111850) and chimeric antigen receptor (CAR) T cell versus 13  days; p < 0.0001). In addition, catumaxomab therapy targeting mesothelin (NCT01583686). patients had fewer signs and ascites associated symptoms than control patients [127]. It was found that patients with soluble EpCAM present in Palliative treatment for malignant ascites ascites had a significantly shorter overall survival; the prog- nostic significance was particularly strong in patients with Advanced and recurrent ovarian cancer is frequently associ- ovarian cancer. However, puncture-free survival and time to ated with formation of malignant ascites in the peritoneal next puncture were not significantly different between solu- cavity. Symptoms related with malignant ascites include ble EpCAM-positive and -negative patients [128]. anorexia, abdominal bloating and pain, dyspnea and respira- Phase III study (CASIMAS/NCT00822809) found that IP tory problems, fatigue and insomnia (rev. in: [122]). Mecha- catumaxomab infusion activates NK cells and macrophages nisms leading to development of ascites are associated with in addition to T cells in ascites and favors CD8(+) T cell intraperitoneal spread of tumor cells; current data indicate accumulation into the peritoneal cavity [129]. In addition, that the effusion accumulates, e.g., as a result of lymphatic catumaxomab, being a mouse/rat antibody, is able to elicit obstruction and increased vascular permeability, mediated human anti-mouse antibody (HAMA) reactions. Symptoms by VEGF and interleukin 6 and 8. Malignant ascites may be can range from a mild allergic reaction, like a rash, to a life- treated with intraperitoneal administration of radioisotopes threatening response, such as renal failure. However, in ovar- or chemotherapy, however, with limited effectiveness. Repet- ian cancer, it was observed that the elevated HAMA levels itive paracentesis provides temporary relief of symptoms, were associated with longer median survival, which may but is associated with several side effects, including loss indicate a superior anti-tumor immune reactivity in HAMA- of protein and hypovolemia, circulatory problems and the positive patients [130, 131]. risk of bowel perforation. The various immunotherapeutic Catumaxomab was also tested for IV application in modalities are currently tested for the management of peri- patients with EpCAM-positive tumor; however, it was shown toneal metastases and ascites, including T cells, checkpoint in phase I study (NCT01320020) that it caused dose depend- inhibitors, antibodies and vaccines (dendritic cell- and virus- ent hepatitis. The first patient receiving 10 μg IV catumax- based), with promising preclinical results (rev. in: [123]). omab experienced fatal acute liver failure which led to the Recent clinical trials suggest that therapies targeted against termination of the study [132]. VEGF and EpCAM result in slower accumulation of ascites and increase the time to the next paracentesis (rev. in: [122]). Aflibercept Catumaxomab Ascites formation is also related with increased vascular permeability caused by VEGF. Aflibercept is a soluble Catumaxomab is a trifunctional rat/mouse hybrid antibody decoy receptor consisting of portions of human VEGF1 and that binds to epithelial cell adhesion molecule (EpCAM) VEGF2 receptors fused to the constant region of human present on tumor cells, to the CD3 antigen on T cells, and IgG1. It is FDA and EMA approved for the treatment of to type I, IIa, and III Fcγ receptors on accessory cells (e.g., wet macular degeneration and metastatic colorectal cancer. natural killer cells, dendritic cells, and macrophages). Catu- A randomized, double-blind, placebo-controlled, phase II maxomab exerts its anti-tumor effects via T cell-mediated trial (NCT00327444) was designed to investigate safety and lysis, antibody-dependent, cell-mediated cytotoxicity, and efficacy of IV aflibercept in inhibition of ascites formation phagocytosis via activation of FcγR-positive accessory cells in patients with advanced chemoresistant ovarian cancer. (rev. in: [124, 125]). In 2009, catumaxomab was approved by Time to next paracentesis was significantly longer in the EMA for the intraperitoneal treatment of malignant ascites experimental group (55.1 days) than in the placebo group in patients with EpCAM-positive cancer, if a standard ther- (23.3 days). There was no significant difference in over - apy is not available. A phase II study (NCT00326885) with all survival between the experimental and placebo groups IP catumaxomab in platinum-resistant ovarian cancer and [133]. The most frequent adverse events were gastrointesti- recurrent symptomatic malignant ascites showed prolonged nal disorders, dyspnea, fatigue or asthenia and dehydration. time to first therapeutic puncture and puncture-free interval, In another phase II study (NCT00396591), median time to and a beneficial effect on quality of life, with an acceptable next paracentesis was 76.0 days, which was 4.5 times longer safety profile [126]. In phase II/III trial (EudraCT 2004- than the baseline interval, before aflibercept (16.8 days). 000723-15/NCT00836654), puncture-free survival was Adverse events included hypertension, headache, anorexia, also significantly longer in the catumaxomab group than in dysphonia, and intestinal perforation (in one patient out the control group (median 46 versus 11 days; HR = 0.254; of 16 enrolled) [134]. Thus, it seems that aflibercept may p < 0.0001) as was median time to next paracentesis (77 be effective for relief the symptoms of malignant ascites, 1 3 32 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 although the major limitation is related with its significant Due to its high prevalence, the majority of preclinical and morbidity (risk of bowel perforation) [133, 135]. clinical studies concern high-grade serous ovarian cancer. Other, more tailored therapies based on individual histo- logical and biological characteristics should be developed Conclusions to target less frequent histological types, such as clear cell or low-grade serous carcinoma. According to the specific Standard treatment for ovarian cancer is surgery, with a goal mutational characteristics of these subtypes, mTOR inhibi- of complete tumor resection, and chemotherapy based on tors and MEK inhibitors would apply, respectively. Better platinum compounds and taxanes. Definition of “optimal molecular and genetic characterization of different subtypes debulking” has changed over years, and now it is clear that of ovarian cancer is required, if we think about personalized survival advantage relies on complete debulking, while leav- treatment. ing any residual tumor, even < 1 cm, is related with worse So far, described biological drugs and new therapeutic prognosis. To achieve complete resection, high-quality sur- approaches were not shown to cure ovarian cancer, but they gical techniques and sophisticated equipment are required, bring the long awaited promise of turning it into a man- indicating the need for centralized treatment for ovarian can- ageable chronic disease. To bring this promise closer, price cer at specialized centers. reduction of the new drugs is awaited. Currently, there are many possible new treatment options Acknowledgements Funding was provided by Narodowe Centrum emerging from recent clinical trials, based both on the modi- Nauki (Grant no UMO-2012/04/M/NZ2/00133). fications of standard approaches and on the addition of a new biological drugs to the standard treatment. Open Access This article is distributed under the terms of the Creative Dose-dense chemotherapy is emerging as an option for Commons Attribution 4.0 International License (http://creativecom- mons.org/licenses/by/4.0/), which permits unrestricted use, distribu- patients with poor performance status. The role of IP chemo- tion, and reproduction in any medium, provided you give appropriate therapy is still not clear, as well as HIPEC. Both approaches credit to the original author(s) and the source, provide a link to the present high level of toxicity/complications and their effi- Creative Commons license, and indicate if changes were made. cacy has to be confirmed unambiguously in phase III trials. From among new drugs, bevacizumab and several PARPi were recently approved for ovarian cancer treatment. They References are still tested in several settings, including maintenance treatment which is itself an emerging approach with grow- 1. 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Advances in ovarian cancer therapy

Cancer Chemotherapy and Pharmacology , Volume 81 (1) – Dec 16, 2017

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References (159)

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Pubmed Central
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© The Author(s) 2017
ISSN
0344-5704
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1432-0843
DOI
10.1007/s00280-017-3501-8
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Abstract

Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment. Keywords Ovarian cancer · Biological drugs · Targeted therapy · Clinical trials Introduction death signals. These are, e.g., anti-angiogenic factors, inhibi- tors of growth factor signaling, polyADP-ribose polymerase Ovarian cancer is the second most common and the most (PARP) inhibitors, or folate receptor inhibitors. In addition, lethal gynecologic malignancy in the western world. So far, there are many immunotherapeutic approaches tested. So far, there is lack of methods recommended for screening and these new agents and therapeutic approaches were not shown early diagnostics of this disease. As a consequence, and also to cure ovarian cancer, but they may improve therapy and due to the absence of early warning symptoms, about 70% of lead to the delay of recurrence or stabilization of the disease. cases is diagnosed at an advanced stage and have bad prog- However, the landscape of ovarian cancer treatment is nosis. Late-stage ovarian cancer is incurable in the majority complicated by heterogeneity of these tumors. Different of cases, but recently it tends to become a kind of chronic histological types of epithelial ovarian cancer have distinct disease. This is mostly due to the progress in surgical tech- cellular origin, diverse mutational spectrum, and thus, dif- nology and contemporary regimes of systemic treatment, as ferent prognosis (rev. in: [1, 2]). Even within one histological well as some new drugs entering the clinic. type, distinct molecular subtypes with different prognoses Currently, there are also many new drugs under develop- can be found (see e.g.: [3, 4]). To address these issues there ment and tested in the ongoing clinical trials aimed to evalu- is a need to better characterize these differences, find reliable ate their efficacy in the treatment of ovarian cancer. New biomarkers and develop appropriate targeted therapies. Even drugs are mostly directed against molecular targets and path- though many studies are aimed at biomarker discovery, and ways that are indispensable for cancer cells proliferation, many putative biomarkers are published, very few are finally tumor growth and escape from immune surveillance and entering the clinics [5]. In this review, we discuss current standard in the therapy for ovarian cancer and new therapeutic approaches, and their Alexander J. Cortez and Patrycja Tudrej contributed equally. present status. * Katarzyna M. Lisowska katarzyna.lisowska@io.gliwice.pl Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice 44-100, Poland Vol.:(0123456789) 1 3 18 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 by clinical symptoms, it is not recommended to implement Standard treatment for ovarian cancer second-line treatment. Deferral of treatment, until clinical symptoms occur, does not worsen the survival [13]. There The standard treatment for ovarian cancer is maximal is consensus that patients with recurrent disease on the cytoreductive surgical debulking followed by the plat- basis of CA125 alone, are eliglible for clinical trials [14]. inum-based chemotherapy. Confirmation of the diagno- sis, as well as staging of the disease is performed during New approaches to the first‑line treatment surgery. In any case, efforts should be made to define the his- Phase III clinical trials indicate that the incorporation of tological type of the tumor, including grading [6]. High- targeted anti-angiogenic treatment with bevacizumab and grade/low-grade scale is currently used, except for endo- weekly dose-dense paclitaxel into first-line management of metrioid ovarian cancer where a three-grade scale is used ovarian cancer can improve survival. Thus, both of these (G1, G2 or G3) [7]. Staging assessment in surgical-path- approaches can be considered new standards-of-care. How- ologic degrees should be done according to current FIGO ever, they have markedly different economic implications recommendations [8]. and place distinct burdens on patients (higher toxicity and According to the Gynaecologic Oncology group intensity of therapy). (GOG), optimal cytoreduction was previously defined as In 2011, based on data from Gynecologic Oncology residual tumor nodules each measuring 1 cm or less in Group protocol 0218 (GOG0218/NCT00262847) and Inter- maximum diameter. However, large multivariate analysis national Collaboration for Ovarian Neoplasia 7 (ICON7/ showed improved progression-free and overall survival NCT00483782) trials, bevacizumab has gained the Euro- for group of patients with complete resection compared pean Medicines Agency (EMA) approval for the first-line with groups with the so-called optimal (between 0.1 and treatment together with standard chemotherapy (carboplatin 1  cm) and suboptimal cytoreduction (p < 0.0001) [9]. and paclitaxel) in women with advanced epithelial ovarian Thus, according to the 2017 ESGO ovarian cancer surgery cancer, fallopian tube cancer or primary peritoneal cancer guidelines, the aim of the frontline surgery is to achieve (OFPC) [15]. However, FDA has not approved bevacizumab complete resection of macroscopic residuals of the disease for the first-line treatment, so far (decision is expected by (complete cytoreduction) [10]. June 2018). After surgery, patients are treated with the intravenous The results of the Japanese GOG 3016 trial platinum/taxane regimes, every 21  days, for six cycles (NCT00226915) suggested that dose-dense weekly pacli- (first-line chemotherapy). In patients with stage IA/IB and taxel plus carboplatin improved survival compared with with G1/G2 tumors, the chemotherapy can be omitted [6]. the conventional regimen. Median progression-free sur- In advanced stages (III/IV), complete cytoreduction vival (PFS) was longer in the dose-dense treatment group is often not possible. The most common reason is the (28.0 months, 95% CI 22.3–35.4) than in the conventional seizure of small bowel mesentery and the lesions in the treatment group (17.2 months, 15.7–21.1; HR 0.71; 95% liver hilum. Patients with inoperable lesions or due to CI 0.58–0.88; p = 0.0015). Overall survival at 3  years poor performance status are first treated with induction was higher in the dose-dense regimen group (72.1%) than (neoadjuvant) chemotherapy. After three cycles of the in the conventional treatment group (65.1%; HR 0.75, chemotherapy, if there is a response to the treatment, the 0.57–0.98; p = 0.03) [16, 17]. On the contrary, the GOG interval debulking surgery (IDS) can be performed, then 0262 trial (NCT01167712) showed that weekly paclitaxel, chemotherapy is continued, up to six cycles [6]. as compared with conventional regimen, did not prolong Treatment outcome is assessed after the completion PFS among patients with ovarian cancer (14.7 versus of first-line chemotherapy. Evaluation of response to the 14.0 months; HR = 0.89; 95% CI 0.74–1.06; p = 0,18). How- treatment is done based on imaging results and accord- ever, it must be mentioned that 84% of analyzed patients ing to RECIST 1.1 criteria (Response Evaluation Criteria received bevacizumab. Among patients who did not receive In Solid Tumors) [11]. The majority of patients respond bevacizumab, weekly paclitaxel was associated with PFS well to the first-line chemotherapy, achieving complete 3.9 months longer than that observed in the conventional response (CR), however, many will develop recurrence. treatment group (14.2 versus 10.3 months; HR = 0.62; 95% For patients with residual disease < 1  cm, the risk for CI 0.40–0.95; p = 0.03). These results support the benefit recurrence is estimated at 60–70%; for women with large- of weekly paclitaxel plus carboplatin, but in the absence of volume residual disease, the risk is estimated at 80–85% bevacizumab administration [18]. International Collabora- [12]. Therefore, patients with CR should be subjected to tion for Ovarian Neoplasia 8 trial (ICON8/ NCT01654146) periodic controls. Increasing level of CA125 can be an is a randomized, three-arm, phase III study designed to early symptom of recurrence, however, if not accompanied investigate again if weekly chemotherapy is more effective 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 19 than standard chemotherapy. ICON8B is investigating the time to relapse is also used as a determinant of tumor sensi- combination of dose-dense chemotherapy and bevacizumab tivity to platinum. Tumors are categorized as: in a subgroup of women with high-risk stage III–IV ovarian cancer [19]. No results of these trials are published so far. – platinum refractory—when tumor progresses during first- There is also ongoing debate whether neoadjuvant chem- line treatment otherapy and IDS may be superior to the massive primary – platinum resistant—recurrence within 6 months after debulking surgery (PDS) in advanced ovarian cancer. The completion of first-line treatment second approach is related with higher mortality and mor- – partially sensitive—recurrence within 6–12 months bidity while the first one may lead to earlier recurrence and – highly sensitive—recurrence after more than 12 months shorter survival. The results of a European Organization for Research and Treatment of Cancer (EORTC) 55971 trial This classification is commonly used, although it is now (NCT00003636) suggested that patients with stage IIIC and generally appreciated that platinum sensitivity is a contin- less extensive metastatic tumors had higher survival with uum, rather than related to arbitrary time points, and cannot primary surgery, while patients with stage IV disease and be accurately determined by progression-free interval (PFI) large metastatic tumors had better survival with neoadju- alone [14]. vant chemotherapy. For patients who did not meet these Selection of second-line chemotherapy protocol is based criteria, both treatment options led to comparable survival on tumor sensitivity to platinum derivatives. Patients that rates [20]. Two new trials: SUNNY (Study of Upfront Sur- have partially- or highly-sensitive tumors can be treated with gery versus Neoadjuvant Chemotherapy in Patients With platinum in combination with other drugs. These patients Advanced Ovarian Cancer, NCT02859038) and TRUST benefit from multi-drug regimens. Usually carboplatin or (Trial on Radical Upfront Surgery in advanced Ovarian Can- cisplatin is used in combination with paclitaxel or pegylated cer, NCT02828618) were recently started, aimed to com- liposomal doxorubicin (PLD) or gemcitabine (with or with- pare the OS after PDS versus IDS following the neoadjuvant out bevacizumab). For treatment of partially-sensitive recur- chemotherapy in patients with FIGO stage IIIB–IVB OFPC. rences, when platinum is not an option (anaphylaxy to plati- A majority of ovarian cancers are chemosensitive and num compounds), PLD with trabectedin can be used [24]. are confined to the surface of the peritoneal cavity for a As was shown in OVA-301 phase III study (NCT00113607), long time. These features decide that ovarian cancer is a the patients with mutation in BRCA gene have longer PFS good target for intraperitoneal (IP) chemotherapy. A recent and OS with this regimen [25]. Trabectedin alone was tested meta-analysis explored the results from nine randomized in MITO15 phase II trial (NCT01772979) for the treatment controlled clinical trials, assessing 2119 women with pri- for recurrent ovarian cancer patients presenting BRCA muta- mary epithelial ovarian cancer, of any FIGO stage, after PDS tion and/or BRCA-ness phenotype (≥ 2 previous responses [21]. Standard intravenous (IV) chemotherapy was compared to platinum). It was concluded that the signature of ‘repeated with chemotherapy that included a component of IP admin- platinum sensitivity’ identifies patients highly responsive istration. Women were less likely to die if they received an to trabectedin which can be valuable alternative option in IP component to chemotherapy (8 studies, 2026 women; patients who present contraindication to receive platinum HR = 0.81; 95% CI 0.72–0.90). IP component chemotherapy [26]. prolonged the disease-free interval (5 studies, 1311 women; The prognosis in patients refractory or resistant to plati- HR = 0.78; 95% CI 0.70–0.86). There was greater serious num treatment is bad. In this group of patients, no benefit toxicity with regard to gastrointestinal effects, pain, fever from combination therapy was shown over monotherapy and infection but less ototoxicity with the IP than the IV with PLD, topotecan, gemcitabine or paclitaxel. The com- route. However, the last IP study, GOG 252, failed to show bination of chemotherapy with bevacizumab significantly an advantage of IP over IV administration [22]. Thus, it is prolongs progression-free survival (PFS), however, only still not clear whether IP chemotherapy increases OS and patients with good performance status are eligible for this PFS. Additionally, the potential for catheter related compli- treatment. cations and toxicity must be considered. In certain cases of recurrent ovarian cancer, resection may be considered. It is eligible for patients who had a complete Treatment of recurrence remission and at least 12 months disease-free period after first-line treatment, and with a likelihood of successful radi- Despite the high response rate to primary treatment, major- cal surgery [14]. The Arbeitsgemeinschaft Gynaekologische ity of patients will develop recurrence [23]. Major option for Onkologie (AGO) Group DESKTOP OVAR I trial, based the treatment of recurrent ovarian cancer is chemotherapy. on retrospective analysis, showed three factors being inde- An important prognostic factor is the time from the end pendently associated with complete resection: macroscopi- of the previous treatment (treatment-free interval, TFI). The cally complete resection at first surgery, good performance 1 3 20 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 status, and the absence of ascites greater than 500 ml. These of chemotherapy. This therapy could also apply for the three factors were combined to the “AGO-score” that was patients with large residual disease after the primary sur- deemed positive if all three criteria were fulfilled. Survival gery and for those who have inoperable lesions. In the analysis showed median OS of 45.2 months in completely latter case, neoadjuvant chemotherapy is given, and the debulked patients, as compared with 19.7 months in patients patients, which will respond, qualify for the cytoreductive with incomplete resection (HR = 3.71; 95% 2.27–6.05; surgery combined with HIPEC. Another eligible group p < 0.0001) [27, 28]. AGO score was verified in a prospec- could include patients in whom laparoscopy revealed tive trial—AGO DESKTOP OVAR II (NCT00368420). malignancy, instead of apparently benign tumor. HIPEC The rate of complete resection was 76%, although negative is not recommended when the disease has disseminated to score might not exclude the possibility to achieve a com- the distant organs outside peritoneum [32]. plete resection. AGO DESKTOP OVAR III (ENGOT ov20/ HIPEC is criticized due to relatively high morbidity and NCT01166737) is randomized, phase III trial comparing mortality of the procedure. Major complications include second-line chemotherapy versus secondary cytoreduc- anastomotic leakage, bowel perforation, intraperitoneal tive surgery followed by chemotherapy, in patients with hemorrhage and wound dehiscence. Reported morbidity platinum-sensitive recurrent ovarian cancer with a positive rates range from 0 to 31.3% (Grade 3 and 4 morbidity AGO-score. OS data are not mature yet, but median PFS was according to the Clavien–Dindo classification) and mor - significantly improved in the experimental arm (14 months tality rates from 0 to 4.2%. Some authors argue that these without versus 20 months with surgery; HR = 0.66; 95% CI numbers are similar to those observed in patients undergo- 0.52–0.83; p < 0.001), even in those patients were complete ing cytoreductive surgery alone [33]. cytoreduction was not achieved [29]. In summary, DESK- So far, most of the results concerning HIPEC in ovar- TOP trials showed that it is possible to select patients who ian cancer are coming from phase I–II or retrospective might benefit from secondary cytoreductive surgery. studies, e.g., a case series analysis (246 ovarian cancer There are several recently completed and ongoing clini- patients with recurrent intraperitoneal lesions or with per- cal trials designed to evaluate new approaches for treatment sistent lesions after systemic treatment) showed that the for recurrent ovarian cancer, e.g. bevacizumab re-treatment median overall survival was 49 months after the maxi- (MITO16MANGO2b/NCT01802749; AGO-OVAR 2.21/ mum cytoreductive surgery and HIPEC [34, 35]. Several NCT01837251), PARPi in combinations with other biolog- randomized studies investigating HIPEC are currently ical drugs, as chemotherapy free option (ENGOT-OV24/ ongoing. A large randomized study (280 patients to be AVANOVA/NCT02354131; NRG004/NCT02446600; enrolled) conducted by the Netherlands Cancer Institute AGO-OVAR 2.28/ENGOT-ov28) [30], PARPi-based OVHIPEC (NCT00426257) and another smaller study options as maintenance therapy (SOLO 2/NCT01874353, CHORINE (NCT01628380) are investigating the benefit ICON 9 [31]), and immune checkpoint inhibitors (ATAL- of HIPEC after IDS for primary ovarian cancer. The larg- ANTE/NCT02891824; AGO-OVAR 2.29 [30]). est ongoing randomized study (444 patients to be enrolled) is the French CHIPOR study (NCT01376752), evaluating the efficacy of HIPEC in patients with platinum-sensitive Hyperthermic intraperitoneal chemotherapy recurrent disease. Two other randomized HIPEC trials (HIPEC) (NCT01539785 and NCT01767675) are also enrolling patients with recurrent disease, and another is investigat- Recently, a combination of cytoreductive surgery and hyper- ing the role of HIPEC after frontline cytoreductive sur- thermic intraperitoneal chemotherapy (HIPEC) is increas- gery (NCT01091636). Most interestingly, randomized ingly used for the management of peritoneal metastases. NCT02124421 trial is comparing the efficacy of cytore- This procedure is now accepted as a standard treatment for ductive surgery with HIPEC, and IV chemotherapy versus pseudomyxoma peritonei, peritoneal mesothelioma and the cytoreductive surgery and post-operative IP and IV chemo- peritoneal metastases from colorectal cancer. At some medi- therapy in primary ovarian cancer. cal centers, HIPEC is also used for the treatment of patients Before the results of these studies will be published, with ovarian cancer. and taking into account toxicity of HIPEC, at present, this In ovarian cancer patients, HIPEC is applied in com- technique cannot be recommended in daily practice. bination with systemic therapy which starts about three weeks after surgery. Cisplatin (optionally with doxoru- bicin) and taxanes are used most frequently for HIPEC. Best results are achieved in the treatment of platinum- sensitive tumors, although it is suggested that eligible are patients with late recurrences and after several lines 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 21 approved bevacizumab, in combination with paclitaxel, New therapeutic targets in ovarian cancer topotecan or pegylated liposomal doxorubicin (PLD) for therapy the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal Angiogenesis inhibitors cancer [37]. Phase III clinical trials investigating bevaci- zumab in ovarian cancer, those completed and still ongo- Angiogenesis is a tightly controlled dynamic process that ing are widely reviewed in [39, 40]. occurs primarily in embryo development, during wound GOG 218 was a double-blind, placebo-controlled, three- healing and in response to ovulation. However, it can be arm trial designed to determine whether the incorporation aberrantly activated during many pathological conditions of bevacizumab to standard chemiotherapy (cisplatin and such as cancer, diabetic retinopathy as well as numer- paclitaxel) in first-line treatment improves progression- ous ischaemic, inflammatory, infectious and immune free survival (PFS) in stage III and IV epithelial ovarian disorders. Among known regulators of angiogenesis are cancer patients who had undergone debulking surgery. The growth factors, matrix metalloproteinases, cytokines, and study evaluated bevacizumab added to standard chemo- integrins. A key player in the development of the patho- therapy followed by bevacizumab maintenance for 22 logical vascular network of tumor is Vascular Endothelial cycles (PFS 14.1 months) versus standard chemotherapy Growth Factor (VEGF) and its signaling pathway. It was (median PFS = 10.3  months). Patients in the third arm initially expected that blocking VEGF signaling in cancer received bevacizumab only with chemotherapy and did not will inhibit angiogenesis and cause tumor shrinkage, due have better clinical outcomes than those treated with stand- to the reduced blood supply. However, a variety of pre- ard chemotherapy alone (PFS = 11.2 months). Relative to clinical studies supported an alternative hypothesis that control group, the HR for progression of death was 0.908 anti-angiogenic agents can transiently ‘‘normalize’’ the (95% CI 0.795–1.040; p = 0.16) with bevacizumab-initiation abnormal structure and function of tumor vasculature to and 0.717 (95% CI 0.625–0.824; p < 0.001) with bevaci- make it more efficient for oxygen and drug delivery [36]. zumab throughout. The lack of a significant difference in In epithelial ovarian cancer, increased VEGF expression PFS between control group and the bevacizumab-initiation has a prognostic value: it is related with tumor grade, stage group implited that bevacizumab must be continued beyond of the disease, and patients’ survival. As VEGF receptors chemotherapy to delay disease progression [41, 42]. are present on the surface of ovarian cancer cells, it seems Another trial investigating the efficacy of standard that VEGF may play a unique role in the development chemotherapy with addition of bevacizumab in patients of this malignancy. By increasing vascular permeability with OFPC was the ICON7 study (NCT00483782). This within peritoneum, VEGF is also responsible for the for- phase III randomized, two-arm trial shown that the use of mation of ascitic fluid in ovarian cancer patients. Conse- bevacizumab given concurrently with 5 or 6 cycles of plat- quently, inhibition of pathological angiogenesis became inum-based chemotherapy and continued for an additional one of the new therapeutic options widely tested in ovarian 12 cycles improved PFS by about 2 months and increased cancer treatment; promising results are shown with beva- the response rate by 20%. The PFS and OS benefits were cizumab, cediranib and pazopanib, as well as aflibercept. much greater among the patients at high risk for progres- sion [improvements of 3.6 months (restricted mean) and 7.8 months (median) respectively], however, bevacizumab Inhibition of VEGF: bevacizumab did expand the range of toxic effects such as hyperthension and bowel perforation [43, 44]. Bevacizumab is a recombinant humanized monoclonal Thus, GOG-0218 and ICON7 trials showed that use of antibody against VEGF. It prevents VEGF from binding to bevacizumab maintenance after standard chemotherapy its receptor; it was shown that bevacizumab leads to nor- prolongs median PFS in patients with advanced epithelial malization of tumor vasculature and reduction of the inter- ovarian cancer [39]. The ongoing phase IV trial MITO16/ stitial tumor pressure, improving effectiveness of standard MANGO-2 (NCT01706120) is intended to explore the therapy. In 2004, it became the first clinically approved potential clinical factors and biological markers identifying angiogenesis inhibitor in the U.S. (approval for the treat- patients that will benefit most from addition of bevacizumab ment, in combination with standard chemotherapy, for to first-line chemotherapy, in terms of progression-free and colon cancer) [37]. In 2011, based on data from GOG0218 overall survival. Phase III BOOST trial (NCT01462890) is and ICON7 trials, bevacizumab has gained European Com- aimed on evaluation of optimal treatment duration of beva- mission approval for the first-line treatment together with cizumab combination with standard chemotherapy. standard chemotherapy in women with advanced OFPC Other studies suggest that the patients with recurrent [38]. In 2014, the Food and Drug Administration (FDA) ovarian cancer may benefit from bevacizumab, regardless 1 3 22 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 of the sensitivity to platinum treatment [45]. The first rand- of cancer [52]. The major survival factor for these cells is omized, open-label, phase III trial combining bevacizumab granulocyte–macrophage colony-stimulating factor 1 (GM- with standard chemotherapy in patients with recurrent plat- CSF1). A trial NCT02923739 is planned that will evaluate inum-resistant ovarian cancer who were given single-agent efficacy of emactuzumab, an inhibitor of GM-CSF recep- chemotherapy alone or with bevacizumab until the disease tor [53], following paclitaxel and bevacizumab, in recurrent progression was AURELIA (NCT00976911). Median PFS platinum-resistant OFPC. was 3.4 months with chemotherapy alone versus 6.7 months On the other hand, bevacizumab may induce hypoxia in with bevacizumab-containing therapy (HR = 0.48, 95% CI the tumor which may contribute to genomic instability, that 0.38–0.60; unstratified log-rank p < 0.001). Median OS was is thought to increase the sensitivity of cells to PARP inhibi- 3.3 months longer in the treatment group; however, it was tors [54]. not statistically significant. Safety analysis showed that The cost-effectiveness of bevacizumab was analyzed hypertension and proteinuria were more common in patients based on the results of ICON7 trial (NCT00483782), which treated with chemotherapy and bevacizumab than in the con- showed that adding bevacizumab (7.5 mg/kg) to standard trol group. Thus, this study showed that adding bevacizumab first-line chemotherapy improves not only PFS but also OS to chemotherapy significantly improved PFS and objective in a pre-specified group of women at high risk of progres- response rate (ORR); there was also trend toward longer sion (in a post hoc subset analysis of 465 high-risk patients, OS [46]. i.e., stage IIIC with residual disease > 1 cm or stage IV, the Another study with final results is OCEANS OS after standard chemotherapy was 28.8 months compared (NCT00434642), a randomized, placebo-controlled, phase with 36.6 months in the treatment group; HR = 0.64; 95% III trial, investigating the efficacy and safety of bevaci- CI 0.48–0.85; p = 0.002). There were three studies, one zumab maintenance after gemcitabine and carboplatin. The conducted from the perspective of the U.S. Medicare sys- patients with platinum-sensitive recurrent ovarian cancer tem [55], one according to the guidelines of U.K. National were treated with 6–10 cycles of chemotherapy and then Health Service [56] and one for Canadian public health care bevacizumab or placebo was continued until disease pro- system [57]. It was estimated that ovarian cancer patients at gression. Median PFS was 4 longer in the treatment group high risk of progression receiving bevacizumab plus stand- (HR = 0.484; 95% CI 0.388–0.605; log-rank p < 0.0001). ard chemotherapy experienced a mean incremental quality- Median OS was comparable between arms. No new safety adjusted life year (QALY) gain of 0.374 years. The incre- signals were identified following prolonged exposure to bev - mental cost-effectiveness ratio (ICER) of bevacizumab was acizumab, however, in experimental group adverse events approximately $167,771 per life-year saved (Medicare). In had greater frequency than in control group [47]. AGO- Canadian analysis, the ICER was $95,942 per QALY, while OVAR17 trial (NCT01462890) is intended to evaluate opti- in British study, it was £48,975, which was considered above mal treatment duration as maintenance. standard cost-effectiveness threshold (£20,000–£30,000 per Three phase III clinical trials of bevacizumab in recur- QALY) accepted by British National Institute for Health and rent ovarian cancer treatment (AURELIA, OCEANS and Care Excellence (NICE). GOG0213/NCT00565851) that investigated in total 1502 In conclusion, bevacizumab has been shown to improve patients, were included into two meta-analyses [48, 49]. PFS for 2–4 months and in some settings also OS, although Both meta-analyses showed that adding bevacizumab to it is associated with higher degree of side effects. A price standard chemotherapy improved ORR, PFS and OS, and it reduction would be required for this product to become cost- had a higher, but manageable incidence of toxicities (graded effective for majority of national health services. So far, 3–4). there were no predictive biomarkers found that could help to It was also tested whether adding bevacizumab to neoad- select patients, who could greater benefit from bevacizumab. juvant carboplatin-paclitaxel helps achieve complete resec- tion at IDS, in patients with advanced initially unresectable Inhibitors of VEGF receptors ovarian cancer (ATHALYA/NCT01739218). Complete resection rate was significantly higher in a group receiving Cediranib additional bevacizumab. The most common grade 3 adverse reactions to treatment occured in 62% of patients in the beva- Cediranib is anti-angiogenic multikinase inhibitor with cizumab group and 63% of patients in the control group. activity against all three VEGF receptors (VEGFR1-3). Post-operative complications occurred in 28 and 36% of the Several phase III trials with cediranib tested against differ - patients, respectively [50]. ent cancers have produced disappointing results; however, It was observed that bevacizumab can induce mac- promising activity has been seen with cediranib in ovar- rophage/monocyte infiltration [51] that has been identified ian cancer. ICON6 trial (NCT00532194) was a randomized as an independent poor prognostic factor in several types phase III double-blind, placebo-controlled study, which 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 23 enrolled women with platinum-sensitive relapsed ovarian PDGFRα/β, with lesser activity against RET, Flt-3 and cancer. It provided the evidence of activity and manage- Src. It has demonstrated significant anti-tumor activity in able toxicity of cediranib added to platinum-based chem- several tumor types in preclinical and clinical studies [63]. otherapy and continued as maintenance therapy for up to In 2014, FDA approved nintedanib for the treatment of 18 months. Median PFS of 11.0 months was observed in idiopatic pulmonary fibrosis. Nintedanib in combination the group treated with cediranib combined with chemo- with docetaxel was approved, in 2014, by the European therapy and then cediranib once-daily maintenance, while Commission for the treatment of adult patients with locally 8.7-month PFS was observed in the group receiving placebo advanced, metastatic or locally recurrent non-small cell during therapy and during maintenance (HR = 0.56; 95% CI lung cancer [64]. 0.44–0.72; p < 0.0001). In a group treated with cediranib in LUME-OVAR 1 (AGO-OVAR 12/NCT01015118) was a combination with chemotherapy then placebo maintenance, randomized, double blind, phase III trial where nintedanib median PFS was 9.9 months. Cediranib toxic effect was the was added to standard first-line chemotherapy, followed by most common cause for discontinuation: the most frequent nintedanib maintenance for a maximum of 120 weeks, in were diarrhea, neutropenia, hypertension, and voice changes patients with advanced epithelial ovarian cancer. This study [58, 59]. demonstrated significant improvement in median PFS in the In conclusion, addition of cediranib yielded an improve- treatment group compared with control group (17.2 versus ment in progression-free survival, albeit with added toxic 16.6 months; HR = 0.84; 95% CI 0.72–0.98; p = 0.0239). A effects. more pronounced PFS benefit was observed in a subgroup analysis in patients with < 1 cm residual tumor (21.1 versus Pazopanib 20.8 months; HR = 0.75; 95% CI 0.61–0.92; p = 0.005). The most common adverse events were gastrointestinal (diar- Pazopanib is a multikinase inhibitor of VEGFR1-3, plate- rhea) and hematological (neutropenia, thrombocytopenia, let-derived growth factor receptor α and β (PDGFRA and anemia). Drug-related adverse events leading to death PDGFRB) and c-Kit. A randomized phase II trial MITO-11 occured in three patients in the nintedanib group and in one (NCT01644825) was investigating the safety and efficacy patient in the placebo group [65]. of pazopanib in combination with paclitaxel in patients A randomized, placebo-controlled, phase II study with platinum-resistant ovarian cancer. PFS was signifi- NCT00710762 checked the maintenance treatment with nin- cantly longer in the experimental group (median PFS—6.35 tedanib following chemotherapy in patients with resistant or versus 3.49 months in placebo group; HR = 0.42; 95% CI partially platinum-sensitive relapsed ovarian cancer. It has 0.25–0.69; p = 0.0002). Adverse events included neutrope- shown a prolongation of PFS at 36 weeks compared with nia, fatigue, leucopenia, hypertension and anemia [60]. placebo (HR = 0.68; 95% CI 0.44–1.07; p = 0.07). There was A phase III study AGO-OVAR16 (NCT00866697) a higher rate of diarrhea, nausea, vomiting and hepatotoxic- designed to evaluate the efficacy and safety of pazopanib ity in the nintedanib group [66]. monotherapy versus placebo in women with OFPC who Nintedanib has shorter half-life (7–19  h) than beva- have not progressed after first-line chemotherapy, has cizumab (14–21  days). GINECO-OV119 (CHIVA/ shown better PFS in patients receiving pazopanib (median NCT01583322) was a randomized, double blind, placebo- PFS = 17.9  months) than in placebo group (median controlled phase II study of nintedanib in addition to neo- PFS = 12.3 months). HR for PFS was 0.77 (p = 0.0021). First adjuvant chemotherapy and IDS in patients with OFPC. No interim analysis of OS did not suggest any benefit. Grade 3 significant difference was observed between the placebo and or 4 adverse events of hypertension (30.8%), neutropenia the nintedanib group in terms of surgery duration as well as (9.9%), liver-related toxicity (9.4%), and diarrhea (8.2%) pre-operative and post-operative complications of the IDS were major side effects [61, 62]. [67]. In conclusion, pazopanib shows advantage toward longer There are currently ongoing phase II trials of nintedanib. PFS, both in the treatment of platinum-resistant/refractory METRO-BIBF (NCT01610869) is a randomized, placebo- ovarian cancer and in platinum-sensitive maintenance; how- controlled trial which primary objective is to explore the ever, further studies are necessary to identify subgroups of efficacy and safety of an all oral combination of nintedanib patients in whom improved efficacy may balance toxicity of and metronomic cyclophosphamide in patients with multi- that treatment. ply-relapsed advanced ovarian cancer, who have completed a minimum of two lines of previous chemotherapy and who Nintedanib for any reason are not suitable for further standard intrave- nous chemotherapy treatments [68]. Another ongoing phase Nintedanib (BIBF1120) is a next generation, potent triple II trial is NCT01669798 which main purpose is to see if nint- angiokinase inhibitor of VEGFR1/2/3, FGFR1/2/3 and edanib can increase the number of women with bevacizumab 1 3 24 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 resistant, persistent, or recurrent epithelial ovarian cancer phenomenon in which two genetic mutations are harmless who do not progress for at least 6 months [69]. when they occur separately, but can result in cell death when Nintedanib in combination with carboplatin and pacli- they arise in combination. The first clinical trials which vali- taxel is an active first-line treatment that significantly dated the clinical significance of this phenomenon involved increases PFS for women with advanced ovarian cancer, the study of PARPi in BRCA1 and BRCA2 (BRCA) muta- but is associated with more gastrointestinal adverse events. tion carriers with advanced solid tumors. In the BRCA wild- type cells, PARP and BRCA proteins participate in DNA Angiopoietin inhibitor repair via different pathways. In the presence of PARP inhi- bition, BRCA and other homologous recombination repair In addition to VEGF, other pathways involved in angiogen- pathway proteins carry out error-free DNA repair. In the esis are also exploited. Angiopoietin 1 and 2 (Ang1/2) bind BRCA-mutated cancer cell, inactivation of both alleles of to Tie-2 receptor, what results in stimulation of endothelial either BRCA1 or BRCA2 leads to homologous recombina- cells proliferation, motility and survival. Trebananib (AMG- tion deficiency (HRD). Treating such cells with a PARPi 386) is a fusion protein that selectively binds Ang1/2, pre- leads to massive DNA damage and cellular lethality (rev. venting signaling through Tie-2. The available results from in: [72]). Also, other tumor-specific homologous recombi - two clinical trials: NCT00479817 [70] and TRINOVA-1 nation defects may be potentially exploited, such as somatic (NCT01204749) [71] were included in meta-analysis [49] BRCA mutations, mutations in ATM, ATR, RAD51, and that showed prolonged PFS (HR = 0.67; 95% CI 0.58–0.77; others [73, 74]. First PARP inhibitor approved for clinical p < 0.00001) and OS (HR = 0.81, 95% CI 0.67–0.99, use was olaparib [75]. p = 0.04) for trebananib in combination with weekly pacli- Multiple trials were designed to evaluate PARP inhibi- taxel in women with recurrent, partially platinum-sensitive tors in ovarian cancer: (1) in a first-line treatment (SOLO1/ or -resistant OFPC. NCT01844986, NCT02470585, PRIMA/NCT02655016, PAOLA1/ NCT02477644, NEO/NCT02489006), (2) in Summary of anti‑angiogenic therapies the treatment of platinum-sensitive relapse (ENGOT- OV24/AVANOVA/NCT02354131, NCI-OVM1403/ Several anti-angiogenic therapies have been shown effective NCT02446600, SOLO3/ NCT02282020, ARIEL4/ in improving PFS of recurrent ovarian cancer with a poten- NCT02855944), (3) in maintenance after chemotherapy tial benet fi of 2–6 months, although with added toxic effects. in platinum-sensitive disease (ENGOT-OV16 NOVA/ Anti-angiogenic drugs are given to unselected patients as NCT01847274, SOLO 2/NCT01874353, ARIEL3/ no predictive markers were found so far. Some data indicate NCT01968213) or (4) in the treatment for platinum-resistant that patients whose tumor blood perfusion or oxygenation disease, and (5) in combination with immune checkpoint increases after the initiation of anti-angiogenic therapy, inhibitors and other biological drugs (widely reviewed in: survive longer than those whose tumor perfusion does not [54, 76–78]). change or decreases [36]. This indicates the directions for further studies. Importantly, when several anti-angiogenic Olaparib therapies (bevacizumab, VEGFR inhibitors and trebananib) were analyzed in two subgroups of (1) platinum-resistant Olaparib (AZD2281) obtained in 2014 an accelerated and (2) platinum-sensitive recurrent ovarian cancer, it was approval by FDA for the treatment for advanced ovarian shown that the PFS improved significantly in both groups, cancer in patients with known or suspected germline BRCA while the OS was clearly better in the platinum-sensitive mutation, who have been treated with three or more prior group, but insignificant in the platinum-resistant group lines of chemotherapy [75]. In the same year, European [49]. These data suggest that it could be possible to improve Medicine Agency (EMA) authorized olaparib as monother- survival with a more personalized use of anti-angiogenic apy in maintenance treatment of patients with platinum sen- agents. sitive, relapsed BRCA-mutated (germline or somatic) high- grade serous epithelial ovarian cancer who are in complete response (CR) or partial response (PR) following platinum- PARP inhibitors based chemotherapy. The approval of olaparib was based on data from Study The Poly(ADP-ribose) Polymerase (PARP) proteins are a 19 (AZ19/NCT00753545), a phase II clinical trial that eval- family of 17 enzymes involved in a wide range of cellular uated its efficacy and safety, compared with placebo, in plat- functions, of which PARP1 and PARP2 are known to be inum-sensitive relapsed high-grade serous ovarian cancer engaged in DNA repair. Cancer treatment with PARP inhibi- patients [79]. The study showed that olaparib maintenance tors (PARPi) exploits the concept of synthetic lethality, a therapy significantly prolonged progression-free survival, 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 25 compared with placebo, in patients with BRCA-mutated phase III trial in patients with germline BRCA-mutated, ovarian cancer (median PFS 11.2 versus 4.3  months; recurrent OC who failed two or more lines of chemother- HR = 0.18; 95% CI 0.10–0.31; p < 0.0001). Adverse events apy, in which olaparib will be compared with single-agent related to olaparib were mostly of grade 1 to 2 and included chemotherapy. nausea, fatigue, vomiting, taste alteration and anorexia, Combined treatment options with a number of other although grade ≥ 3 adverse events were most frequent in the agents are also being assessed. Olaparib was studied in olaparib group (40%) than in the placebo group (22%). The combination with the anti-angiogenic multikinase inhibi- most pronounced were nausea (2 versus 0%), fatigue (7 ver- tor, cediranib. Median PFS was 17.7 months for women sus 3%), anemia (5 versus 1%), neutropenia (4 versus 1%). treated with cediranib and olaparib (n = 44) compared with In several other trials, olaparib was tested as maintenance 9.0 months for those treated with olaparib alone (n = 46; therapy alone or in addition to standard chemotherapy, as HR = 0.42; p = 0.005) [81, 83]. OS data were not mature; prior- and post-surgery treatment, and in combination with however, there was a trend toward longer OS in the combi- different new drugs. The SOLO1 study (NCT01844986), nation group. Treatment-related adverse effects were more conducted in collaboration with the Gynecologic Oncology common in patients treated with cediranib plus olaparib than Group (GOG), was designed to assess the role of mainte- with monotherapy. nance olaparib after frontline chemotherapy for OC patients Recently, results of phase I studies of olaparib in combi- with germline BRCA mutations. SOLO2, performed in col- nation with the PI3K inhibitor BKM120 (NCT01623349) laboration with the European Network of Gynaecological [84] and the AKT inhibitor AZD5363 (NCT02208375) [85] Oncological Trial (ENGOT) Groups, was investigating have been reported with evidence of activity in OC. the role of maintenance olaparib after two or more lines of chemotherapy for OC patients with germline BRCA muta- Niraparib tions. Both trials are randomized, double-blind, placebo- controlled. The primary endpoint was investigator-assessed Niraparib (MK4827) is an oral, selective PARP-1 and -2 PFS which median was 19.1 months in the treatment group inhibitor that was shown in preclinical studies to induce syn- versus 5.5 months in the placebo group (HR 0.30; 95% CI thetic lethality in tumors with loss of PTEN and BRCA1 or 0.22–0.41; p < 0.0001). The results of blinded independ- BRCA2 function [77]. Clinical studies showed that niraparib ent central review of SOLO2 study were shown in March significantly improved PFS in patients with platinum-sensi- 2017 at the Society of Gynecologic Oncology Annual Meet- tive recurrent ovarian cancer, regardless of BRCA mutation ing on Women’s Cancer, indicating significantly longer PFS or HRD status, although its efficacy was highest in patients (30.2 months with olaparib versus 5.5 months with placebo; with BRCA mutations. HR = 0.25 (95% 0.18–0.35), p < 0.0001) [80]. Based on In the end of April 2017, niraparib obtained FDA approval these data the FDA has granted a priority review to a new for the maintenance treatment of patients with recurrent OC application for olaparib as a maintenance therapy in relapsed who are in a CR or PR to platinum-based chemotherapy patients with platinum-sensitive ovarian cancer. [86]. Approval was based upon data from the international Pooled data from six olaparib trials (two phase I trials and phase III ENGOT-OV16/NOVA (NCT01847274) trial, a four phase II studies) that recruited women with relapsed double-blind, placebo-controlled study that enrolled 553 disease were used to explore the activity of olaparib in rela- patients. Approximately two thirds of study participants tion to the number of prior treatment lines in patients with did not have germline BRCA mutations. PFS in a group germline BRCA- mutated ovarian cancer. In the pooled pop- with germline BRCA mutations was 21.0 months, while in ulation of 273 patients who had been administered three or the placebo group—5.5 months (p < 0.0001). In the group more lines of prior chemotherapy, the objective response with non-mutated BRCA but with HRD positive score, rate (ORR) was 36% with a 7.4 month median duration [81]. PFS was 12.9 months while in placebo group—3.8 months Olaparib is also under investigation in combination with (p < 0.0001). Even in a group without mutations and HRD- chemotherapy. In a randomized, open-label, phase II study negative, PFS was longer in niraparib-treated patients (6.0 (NCT01081951), patients with platinum-sensitive, recurrent versus 3.9 months, p = 0.02). Niraparib reduced the risk OC received either olaparib with paclitaxel and carboplatin, of progression or death by 74% in patients with germline followed by olaparib maintenance, or paclitaxel and carbo- BRCA mutations (HR = 0.26) and by 55% in patients with- platin without any maintenance treatment. PFS was slightly out mutations (HR = 0.45). The most common grade 3/4 but significantly improved for the olaparib group versus adverse reactions to niraparib in the NOVA trial included chemotherapy alone (12.2 versus 9.6 months; HR = 0.51, thrombocytopenia (29%), anemia (25%), neutropenia (20%), 95% CI 0.34–0.77; p = 0.0012), particularly in patients with and hypertension (9%). The majority of hematologic adverse BRCA mutations (HR = 0.21, 95% CI 0.08–0.55; p = 0.0015) events were successfully managed via dose modification [82]. SOLO3 (NCT02282020) is an ongoing randomized, [87]. 1 3 26 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 The ongoing development program for niraparib includes BRCA mutation, BRCA-wild type/LOH-high, BRCA- a Phase III trial in patients who have received first-line treat- wild type/LOH-low and BRCA-wild type/LOH indetermi- ment for ovarian cancer (PRIMA/NCT02655016) and a nate) was 10.8 months (HR = 0.37, p < 0.0001), while in registrational Phase II trial in patients who have received the placebo group median PFS was 5.4 months. The most multiple lines of treatment for ovarian cancer (QUADRA/ common grade 3 or higher adverse reactions to rucaparib NCT02354586). Several combination studies are also in the ARIEL3 trial included anemia (18.8 versus 0.5% underway, including trials of niraparib plus pembrolizumab in the placebo group) and elevated alanine/aspartate ami- (TOPACIO/NCT02657889) and niraparib plus bevacizumab notransferase (10.5 versus 0%) [91]. In the ongoing ARIEL4 (ENGOT-OV24/AVANOVA/NCT02354131). (NCT02855944) confirmatory study, the primary purpose is to assess the efficacy and safety of rucaparib versus standard Rucaparib chemotherapy in the treatment for relapsed ovarian cancer in patients with BRCA mutation. Rucaparib (CO338, AGO14699, PF01367338) is an orally administered, small molecule-based PARP-1, -2 and - 3 Other PARP inhibitors inhibitor. In December 2016, the FDA granted an acceler- ated approval for rucaparib as monotherapy for the treatment There are several other PARPi currently tested for the of patients with advanced ovarian cancer associated with treatment for different cancers, including ovarian. Veli- BRCA mutations (germline and/or somatic) who have been parib (ABT888) is an orally administered inhibitor of both treated with two or more lines of chemotherapy [88, 89]. PARP-1 and - 2 that is extensively studied (currently there ARIEL2 (NCT01891344) was a phase II biomarker are 26 registered trials concerning ovarian cancer), in com- study that assessed if loss of heterozygosity (LOH) level, bination with chemotherapy, and as a single agent (rev in: can predict response to rucaparib. ARIEL2 enrolled patients [77]). with platinum-sensitive, recurrent, high-grade serous or Talazoparib (BMN673) has been very promising in pre- endometrioid ovarian cancer after one or more lines of clinical studies, but it is currently tested mostly in the phase platinum-based chemotherapy and whose last treatment I trials. Phase II trial (NCT 02326844) which tested tala- was platinum-based. The primary objective was to evaluate zoparib as monotherapy for patients with BRCA-mutated clinical activity of rucaparib in three subgroups, delineated ovarian cancer who had prior PARPi treatment has been by BRCA mutation and HRD status (expressed by LOH terminated. level, quantified with a next-generation sequencing assay): (1) BRCA-mutated, (2) BRCA-wild type/LOH-high and (3) Summary of PARP inhibitors BRCA-wild type/LOH-low. Median PFS after rucaparib treatment in a group with BRCA mutations was 12.8 months PARPi (olaparib, niraparib) have recently become a standard (9.0–14.7), in the LOH high group was 5.7 months (5.3–7.6), of care for patients with recurrent BRCA-mutated ovarian and in the LOH low group was 5.2 months (3.6–5.5). PFS cancer. In addition, it was shown that olaparib significantly was significantly longer in the BRCA mutant and LOH high improved PFS in patients with platinum-sensitive recurrent groups compared with the LOH low group. These results ovarian cancer, regardless of BRCA mutation. Niraparib suggested that assessment of tumor LOH can be used to showed improved PFS in the same setting, regardless of identify patients with BRCA wild-type platinum-sensitive BRCA mutation and HRD status. It suggests that although ovarian cancers who might benefit from rucaparib. efficacy of both agents is highest in BRCA-mutated popula - The most common grade 3 adverse reactions to rucaparib tion, other patients may benefit, too. Other settings are cur - in the ARIEL2 trial included anemia or low hemoglobin rently extensively tested, e.g., PARPi in primary treatment (22%), elevated alanine aminotransferase or aspartate ami- and in maintenance after primary treatment, PARPi as mon- notransferase (12%), small intestine obstruction (5%), malig- otherapy or combined with chemotherapy and/or with other nant neoplasm progression (5%) [90, 91]. biological agents. However, the utility of PARPi in combina- Rucaparib was also tested as maintenance treatment for tion with chemotherapy is concerned with enhanced toxic- platinum-sensitive patients, stratified into three groups in ity, thus more promising are strategies combining PARPi the ARIEL3, a double-blind, placebo-controlled, phase III with anti-angiogenic agents, or with inhibitors of the P13K/ trial that enrolled 564 women (NCT01968213). PFS after AKT pathway and new generation of immunotherapy (rev. rucaparib treatment in a group with BRCA mutations was in: [92]). 16.6  months (HR = 0.23, p < 0.0001), in the HRD-group As only BRCA1 or BRCA2 mutations and cisplatin (including patients with BRCA mutation or BRCA wild sensitivity are accepted predictors of a response to PARPi. type/LOH-high) was 13.6 months (HR = 0.32, p < 0.0001), Thus, it is now widely accepted that BRCA testing should and in the “intent to treat” group (including patients with be offered for all women with ovarian cancer. 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 27 Exact characteristics of long-term responders is still to may form homodimers or may cooperate by forming het- be recognized and a better HRD test is needed [93]. Astra erodimers, both types of interactions resulting in an active Zeneca AZ HRR test examines mutations in 15 genes related signaling trough Ras-Raf-MAPK and PI3K/AKT pathways, with homologous repair (BRCA1/2, ATM, RAD51B/C/D, what leads to the increased cell proliferation and inhibition RAD54L, FANCJ, FANCL, FANCN, BARD1, CHEK1/2, of apoptosis. Thus, ErbB proteins are potential therapeutic CDK12, PPP2R2A). However, many of these mutations are targets in many cancers. of low frequency and some confer only very slight sensitiv- In ovarian cancer, high EGFR expression was shown to ity to PARPi. Myriad MyChoice test is based on the assess- be related with shorter disease-free survival (DFS) and OS. ment of three independent indicators of genome instabil- Unfortunately, none of EGFR inhibitors (erlotinib, cetuxi- ity: telomeric allelic imbalance, large-scale transitions, and mab or lapatinib) showed promising results in clinical trials LOH. Assay is based on whole genome profiling of single investigating its efficacy in ovarian cancer treatment. Disap- nucleotide polymorphisms (SNPs) [51, 94]. pointing results were also achieved with pertuzumab which Although current data indicate that PARPi are well toler- is directed against HER2. ated, careful assessment of moderate and late-onset toxicities is required, as these drugs are intended to be taken for a long periods of time. Folate receptor α inhibitors Clinical studies suggest that PARPi may have a greater impact on prolonging PFS in BRCA-mutated patients then Folate receptor alpha (FRα) is glycosylphosphatidylinositol anti-angiogenic therapy. In addition, PARPi are better toler- protein, anchored in the cell membrane. In physiological ated, and have a benefit of oral administration. However, conditions, it is present only in some polarized epithelia cost-effectiveness of this therapy is currently challenging; and its expression is strictly confined to the apical/luminal e.g., according to the appraisal by NICE, the ICER for cell surface. It is, however, frequently overexpressed in the olaparib maintenance in platinum-sensitive relapsed ovarian tumors of epithelial origin, where it loses its polarized loca- cancer versus routine surveillance is likely to be more than tion and is present on the entire cell surface. Thus, FRα is a £92,000 per QALY gained [90]. It was also suggested by potential biomarker for cancer cells detection and a promis- these authors that with limited health care resources, future ing therapeutic target (rev. in: [97]). clinical trials should incorporate a prospective collection of Folates play an essential role in the biosynthesis of costs, long-term treatment toxicity, and quality of life. purines and thymidine, which are required for DNA synthe- Cost-effectiveness analysis of olaparib and rucaparib was sis, methylation and repair. The majority of folate transport recently presented on American Society of Clinical Oncol- is mediated by low affinity solute transporters, while the ogy 2017 Annual Meeting. Platinum-based combinations proteins from FR family assure high affinity transport. Thus, were found the most cost-effective at $1672/PFS month, targeting FRα does not block completely folate intake and as compared to non-platinum agents ($6688/month), bev- this is not a major mechanism responsible for anti-cancer acizumab-containing regimens ($12,482/month), olaparib activity of this approach, which is rather related with anti- ($13,3731/month), and rucaparib ($14,034/month). Consid- body-dependent cellular cytotoxicity [98]. ering a cost of $114,478 for olaparib and $137,068 for ruca- Ovarian cancer is probably the tumor in which FRα is parib prior to progression, costs associated with PARPi were most frequently overexpressed. It is estimated that over 80% 7.1–8.3 times higher than platinum combinations [95, 96]. of serous ovarian cancers show FRα expression Lutz [99]. In The authors of this report commented that “while the data on addition, expression level of FRα has been also correlated the PARP inhibitors is promising, the unfortunate nature of with tumor stage and higher histological grade, with poor new therapies is their inherent associated high costs reflect- response to chemotherapy, and worse survival. Moreover, ing the high costs of development”. FRα expression is not affected by chemotherapy itself (rev. in: [97, 100]). FR expression can be exploited therapeutically by sev- EGFR tyrosine kinases inhibitors eral strategies, e.g., using specific antibodies or antibody- like binders to target FRα itself. An example is farletu- ErbB family consists of four closely structurally and func- zumab, which is currently tested in several clinical trials. tionally related tyrosine kinases: the Epidermal Growth Other possibility is to use an antibody-drug conjugates to Factor Receptor (EGFR/HER1/ErbB1), Human Epidermal deliver a drug of choice into cancer cell. IMGN853 (mir- Growth Factor Receptor 2 (HER2/neu/ErbB2), HER3/ErbB3 vetuximab soravtansine) is a representative, currently and HER4/ErbB4. The main ligand of ErbB1 (EGFR) is Epi- entering into clinical trials. However, most extensively dermal Growth Factor (EGF). ErbB2 has no known ligands, evaluated are folate–drug conjugates which have been while ErbB3 has no active kinase domain. ErbB receptors used in several preclinical studies to deliver toxic proteins, 1 3 28 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 radiopharmaceuticals, antisense oligonucleotides, chemo- help to define a subgroups of patients that will benefit from therapeutic agents and their liposomal formulations, to the this treatment. cancer cells [rev. in: [99]]. A conjugate which is currently tested in clinical trials is vintafolide. Vintafolide FRα targeting may be also useful for imaging purposes: a small molecule targeting FRα conjugated with technetium- Vintafolide (MK-8109, EC145) is a water-soluble folate 99m-based imaging agent (99mTc-etarfolatide, FolateScan) conjugated with microtubule destabilizing agent, a vinca is tested (NCT03011320) for identification of cells express- alkaloid derivative, desacetylvin-blastinemonohydrazide ing FRα [97]. (DAVLBH). DAVLBH disrupts the formation of the mitotic In addition, anti-FRα vaccines (NCT02111941; spindle, which leads to cell cycle arrest and cell death. NCT02764333) and FRα-targeting T cell therapies are Folate–drug conjugate binds to FRα and enters the cell via exploited (rev. in: [98, 100]). endocytosis [99]. Early clinical evidence suggested that vin- tafolide may have anti-tumor effect in women with advanced ovarian cancer [104]. Open-label phase II PRECEDENT Farletuzumab trial (NCT00722592) evaluated the effects of adding vinta- folide to PLD in patients with platinum-resistant recurrent Farletuzumab (MORAb-003) is a humanized monoclonal ovarian cancer. Median PFS was 5.0 months in experimental antibody with high affinity for FRα [99]. Preclinical stud- group versus 2.7 months for PLD alone. The study showed ies suggest that farletuzumab exerts its anti-tumor activ- that FRα-positive patients (based on etarfolatide imaging) ity through different mechanisms, either by promotion of benefited from vintafolide and PLD combination therapy, tumor cell lysis by antibody-dependent cellular cytotoxicity whereas patients with FRα-negative tumors did not [103]. or complement-dependent cytotoxicity. Other mechanisms Unfortunately, phase III PRECEDENT trial (NCT01170650) are based on induction of sustained autophagy, resulting in has been discontinued because the experimental arm did not a decreased proliferation, or inhibition of the interaction meet the pre-specified primary outcome for PFS improve- between FRα and lyn kinase, leading to reduced intracellu- ment [105]. lar growth signaling [101]. Phase I/II clinical trials demon- strated feasibility and safety of farletuzumab; the most com- Mirvetuximab soravtansine (IMGN853) mon adverse events were hypersensitivity reactions, fatigue and diarrhea. A phase II trial (NCT00318370) showed that IMGN853 belongs to the class of antibody-drug con- farletuzumab with carboplatin and taxane may enhance the jugates; it consists of an anti-FRα antibody coupled to a response rate and duration of response in platinum-sensitive highly potent cytotoxic maytansinoid payload. It is currently ovarian cancer patients with first relapse after remission of tested in three phase I trials (NCT02996825, NCT01609556, 6–18 months [102]. Unfortunately, the efficacy data in phase NCT02606305) and one phase III trial (NCT02631876), III trials are conflicting [103]. One phase III randomized, which is an open-label, randomized study designed to com- placebo-controlled trial (NCT00738699) was designed pare the safety and efficacy of IMGN853 to single-agent investigate farletuzumab in combination with weekly pacli- chemotherapy in women with platinum-resistant FRα- taxel in patients with platinum-resistant recurrent or refrac- positive advanced EFPC. tory EOC. This study was terminated because interim analy- sis showed that it was unlikely to meet primary endpoint of two-year PFS. Immunotherapy for ovarian cancer Another phase III randomized, double-blind, placebo- controlled trial (NCT00849667) was aimed to compare the Cancer immunotherapy includes different approaches aimed efficacy and safety of six cycles of carboplatin and taxane to enhance an individual’s own immune system to elimi- with and without weekly farletuzumab in patients with a nate tumor cells. EOC is an immunogenic tumor that can first platinum-sensitive relapse of EOC. No significant dif- be recognized by the host immune system; tumor reactive ferences in PFS among the treatment arms were observed. T cells and antibodies can be detected in the blood, tumor However, post hoc exploratory analysis revealed a trend and ascites of EOC patients with advanced disease (rev. in: toward improved PFS in some patient subsets [101]. It is [106]). It was also shown that higher tumor infiltration with suggested that lack of improvement in PFS in the above stud- CD8 + T cells (tumor-infiltrating lymphocytes—TILs) is ies was due to the fact that patients were recruited without positively correlated with patients survival [107, 108]. analyzing FRα expression level. On the other side, useful- Several approaches were designed for either enhancing ness of FRα as a predictive biomarker is unclear. Thus, fur- unspecific immune response or inducing specific adaptive ther studies are necessary to identify biomarkers that will response against tumor antigens, including passive or active 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 29 immunotherapy (widely reviewed, e.g., in: [109–111]). combined with WT1 analog peptide vaccine plus mon- Unfortunately, although some of the studies reported a tanide (an incomplete Freund’s adjuvant), and GM- positive outcome from the treatment of ovarian cancer with CSF (a potent stimulator of dendritic cell maturation) specific immunotherapy, these results were not significant in (phase I, NCT02737787). Nivolumab is also investi- meta-analysis by Alipour et al. 2016 [112]. More promising gated in combination with oregovomab (anti-CA125 seem to be newer approaches involving immune checkpoint antibody) in phase I/II study (NCT03100006); with inhibitors, alone or in combination with other biological bevacizumab (phase II, NCT02873962); or ipilimumab therapies and drugs [110]. (NCT02498600, NCT02834013, NCT02923934) and in combination with epacadostat (an inhibitor of indoleam- Checkpoint inhibitors and immune modulators ine 2,3-dioxygenase; IDO1) (phase I/II, ECHO-204/ NCT02327078). In physiological conditions, distinct immune checkpoint – Ipilimumab is a recombinant, human monoclonal proteins either stimulate or block T lymphocyte activity, to antibody targeting CTLA-4 that is FDA-approved for regulate the balance between immune response and toler- the treatment for melanoma. It is tested in monother- ance. Checkpoint receptors such as Cytotoxic T Lympho- apy for recurrent platinum-sensitive ovarian cancer cyte Associated Protein 4 (CTLA-4) and Programmed Cell (NCT01611558) and in combination with nivolumab Death Protein 1 (PD-1) act to reduce autoimmune responses (see above). against self-tissues. In cancer patients their activity is often – Avelumab is a humanized monoclonal anti-PD-L1 anti- increased, what results in the impaired natural anti-cancer body that does not block PD-1 interaction with PD-L2. immunity. The rationale behind using immune-checkpoint In March 2017, it was FDA approved for the treatment inhibitors is to unblock anti-tumor responses. Alternatively, of Merkel cell skin carcinoma. It is currently tested in activating stimulatory molecules, may be implemented to two Phase III trials for ovarian cancer: one for first-line enhance pre-existing anti-cancer immune responses [109, therapy in combination with carboplatin and paclitaxel 113, 114]. (Javelin ovarian 100/NCT02718417) and the other for the Two factors were recognized, so far, that help predict treatment for recurrent platinum-resistant/refractory dis- tumor response to immune checkpoint inhibitors, namely ease, in combination with PLD versus PLD alone (Javelin accessibility of the tumor by effector immune cells and reli - ovarian 200/NCT02580058) ance of tumor cells on immune checkpoint pathways. The – Atezolizumab is a humanized, monoclonal antibody tar- surrogate markers for these features are, e.g., the presence geting PD-L1 that is FDA-approved for the treatment of of TILs in the tumor and PD-1 ligand (PD-L1) expression, bladder/urothelial carcinomas. It is tested in several trials respectively. Based on these markers, it is estimated that for recurrent ovarian cancer, e.g., phase III randomized, over a half of high-grade serous ovarian cancers represents double-blinded trial ATALANTE (NCT02891824) that a pattern of adaptive immune resistance and is likely to is aimed to evaluate atezolizumab versus placebo in respond to immune checkpoint inhibitors, while in other his- combination with platinum-based chemotherapy and tological types such phenotype is less frequent (about 25% of bevacizumab. Phase II randomized trial (EORTC-1508/ clear cell and mucinous cancers) or absent (low-grade SOC) NCT02659384) is intended to investigate atezolizumab [Gaillard et al. 2016]. with bevacizumab or acetylsalicylic acid in patients with Currently, several immune checkpoint inhibitors are in recurrent platinum-resistant ovarian cancer. Phase II/III early phase testing for ovarian cancer treatment (phase I and randomized study (NCT02839707) is evaluating safety II) (rev in: [110, 113]). and efficacy of PLD with atezolizumab and/or bevaci- zumab. – Pembrolizumab is an anti-PD-1 antibody, FDA-approved – Durvalumab (MEDI4736) is a monoclonal antibody for the treatment for melanoma and NSCLC. Currently, it against PD-L1. It is currently evaluated in phase I/II is tested as monotherapy (NCT02608684, NCT02440425, study (NCT02484404) in combination with olaparib NCT02537444, Keynote-100/NCT02674061) or in com- and cediranib in advanced or recurrent ovarian cancer; bination with PLD (NCT02865811) or with bevacizumab in phase I/II study (NCT02431559) in combination and cyclophosphamide (NCT02853318) in patients with with PLD and motolimod (a Toll-like receptor 8 ago- recurrent ovarian cancer. Pembrolizumab is also evalu- nist), in recurrent platinum-resistant ovarian cancer; in ated in combination with carboplatin and paclitaxel as a phase I study (NCT01975831) in combinantion with first-line chemotherapy (NCT02520154, NCT02766582); tremelimumab (a human monoclonal antibody against – Nivolumab is an anti-PD-1 antibody, FDA approved CTLA-4); and in combination with azacitidine (phase I for the treatment for melanoma. It is currently tested study METADUR/ NCT02811497) in platinum-resistant in patients with advanced cancers, including OFPC, ovarian cancer. Durvalumab is also tested in combination 1 3 30 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 with TPIV200/huFR-1 (a multi-epitope anti-folate recep- fragments of diphtheria toxin and human interleukin-2 were tor vaccine), in patients with platinum-resistant ovarian tested in already completed study NCT00703105, but no cancer (phase II study, NCT02764333). Another phase I/ results were published so far. CVac, a MUC1-targeted DC II study (NCT02726997) is aimed to evaluate pharmaco- vaccine, was tested in CAN-003/NCT01068509 study. A dynamics and feasibility of durvalumab in combination variable CVac-derived, mucin 1-specific T cell response with chemotherapy for the first-line treatment of ovarian was measured. PFS was not significantly longer in the treat- cancer. ment group, but one subgroup (patients in second remission) showed an improved PFS and OS [118]. Another study on So far, preliminary clinical data show limited efficacy CVac (NCT01617629) was completed, but no results were of these agents in ovarian cancer with objective response published, so far. rates of 10–15% and with some durable responses. Thus, it Other trials include phase I study (NCT01376505) remains to be established, why some patients do not respond on a vaccine composed of two HER2 peptides: MVF- to immune checkpoint inhibitors and to find predictive bio- HER-2(597–626) and MVF-HER-2 (266–296) tested in markers. Another task is to determine the best combination different metastatic tumors, including OC; a study on therapy [113]. ID-LV305 vaccine, consisting of lentiviral vector targeting DCs, and containing sequences encoding the NY-ESO-1 Therapeutic vaccines antigen (NCT02122861); a NCT02387125 trial on CMB305, a combination product composed of a cancer vaccine con- Therapeutic cancer vaccines are intended to induce cell- taining an NY-ESO-1 antigen (LV305) and glucopyranosyl mediated immunity, so that immune cells are activated to adjuvant in lipid emulsion (G305). A mixed bacteria vaccine identify and eliminate malignant cells. For this purpose, (MBV/Coley’s toxin) was tested as non-specific immuno- selected tumor-associated antigens are delivered using dif- therapy in patients with different tumors expressing NY- ferent approaches; there are cell-based vaccines, peptide/pro- ESO-1 antigen in phase I study (NCT00623831). Ten of tein, epigenetic, and genetic vaccines tested against different 12 patients showed a consistent increase in serum IL-6 lev- tumors, which are either given alone or in combination with els and body temperature. A subgroup of patients showed different adjuvants, such as cytokines or other stimulatory increasing levels of TNF-α, IFN-γ, and IL1-β [119]. The factors (reviewed in: [106, 115, 116]). MVA-5T4 vaccine (a recombinant modified vaccinia Ankara In ovarian cancer, there are several tumor-associated anti- viral vector encoding the 5T4 fetal oncoprotein) is tested in gen molecules found on the surface or inside the cells that TRIOC/NCT01556841 trial. A phase II/III trial (MIMOSA/ can potentially serve as targets for immune recognition and NCT00418574) on abagovomab (a murine anti-idiotypic response; these are, e.g., CA125, p53 protein, FRα, HER2, antibody against CA-125) in maintenance therapy was ter- and cancer–testis antigens, like MAGE-A4 and NY-ESO-1 minated, as no benefit on primary end point (recurrence-free [117]. Currently, there are mainly pilot and phase I or II survival) was observed [120]. trials on the use of therapeutic vaccines in ovarian cancer (widely reviewed in: [106]). For patients with OFPC there are ongoing studies on p53- Adoptive T cell transfer MVA vaccine, based on modified vaccinia virus expressing p53 protein (NCT02275039); on an autologous oxidized A third major trend of immunotherapy for ovarian cancer tumor cell lysate vaccine given with montanide and Poly- is adoptive T cell transfer. This therapy uses autologous or ICLC (a Toll-like receptor 3 stimulant) (NCT02452775); allogeneic anti-tumor lymphocytes to induce cancer regres- on gemogenovatucel-T vaccine that consists of autologous sion. In this approach, peripheral blood lymphocytes (PBLs) tumor cells electroporated with FANG vector encoding GM- are isolated via apheresis, than tumor-specific lymphocytes CSF, and a bi-shRNA targeting furin convertase, thereby are selected and expanded in vitro, then re-introduced into downregulating endogenous immunosuppressive TGF-β1 the patient. Alternatively, PBLs can be genetically modified and β2 (VITAL/NCT02346747); and on IDO1 inhibitor to enhance their anti-tumor activity (rev. in: [109, 121]). INCB024360, in combination with CDX-1401 (a fusion pro- Several phase I and II trials of adoptive T cell transfer tein, consisting of NY-ESO-1 antigen and a human mono- are currently underway for patients with advanced cancers, clonal antibody against the endocytic dendritic cell receptor, including ovarian, e.g., treatment with NY-ESO-1 antigene- DEC-205) and Poly-ICLC (NCT02166905). reactive TCR (retroviral vector transduced) autologous PBLs In ovarian cancer, the tumor-specific intra-nodal autol- alone (NCT01567891), or with NY-ESO antigene-pulsed ogous alpha-DC1 vaccines are tested in phase I/II study dendritic cells as a vaccine (NCT01697527). Other ongo- NCT02432378. A dendritic cell (DC) vaccine and ontak ing phase I/II trials are investigating anti-MAGE-A3 anti- (denileukin diftitox), a cytotoxic fusion protein containing gene-reactive TCR (retroviral transduced) autologous PBLs 1 3 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 31 (NCT02111850) and chimeric antigen receptor (CAR) T cell versus 13  days; p < 0.0001). In addition, catumaxomab therapy targeting mesothelin (NCT01583686). patients had fewer signs and ascites associated symptoms than control patients [127]. It was found that patients with soluble EpCAM present in Palliative treatment for malignant ascites ascites had a significantly shorter overall survival; the prog- nostic significance was particularly strong in patients with Advanced and recurrent ovarian cancer is frequently associ- ovarian cancer. However, puncture-free survival and time to ated with formation of malignant ascites in the peritoneal next puncture were not significantly different between solu- cavity. Symptoms related with malignant ascites include ble EpCAM-positive and -negative patients [128]. anorexia, abdominal bloating and pain, dyspnea and respira- Phase III study (CASIMAS/NCT00822809) found that IP tory problems, fatigue and insomnia (rev. in: [122]). Mecha- catumaxomab infusion activates NK cells and macrophages nisms leading to development of ascites are associated with in addition to T cells in ascites and favors CD8(+) T cell intraperitoneal spread of tumor cells; current data indicate accumulation into the peritoneal cavity [129]. In addition, that the effusion accumulates, e.g., as a result of lymphatic catumaxomab, being a mouse/rat antibody, is able to elicit obstruction and increased vascular permeability, mediated human anti-mouse antibody (HAMA) reactions. Symptoms by VEGF and interleukin 6 and 8. Malignant ascites may be can range from a mild allergic reaction, like a rash, to a life- treated with intraperitoneal administration of radioisotopes threatening response, such as renal failure. However, in ovar- or chemotherapy, however, with limited effectiveness. Repet- ian cancer, it was observed that the elevated HAMA levels itive paracentesis provides temporary relief of symptoms, were associated with longer median survival, which may but is associated with several side effects, including loss indicate a superior anti-tumor immune reactivity in HAMA- of protein and hypovolemia, circulatory problems and the positive patients [130, 131]. risk of bowel perforation. The various immunotherapeutic Catumaxomab was also tested for IV application in modalities are currently tested for the management of peri- patients with EpCAM-positive tumor; however, it was shown toneal metastases and ascites, including T cells, checkpoint in phase I study (NCT01320020) that it caused dose depend- inhibitors, antibodies and vaccines (dendritic cell- and virus- ent hepatitis. The first patient receiving 10 μg IV catumax- based), with promising preclinical results (rev. in: [123]). omab experienced fatal acute liver failure which led to the Recent clinical trials suggest that therapies targeted against termination of the study [132]. VEGF and EpCAM result in slower accumulation of ascites and increase the time to the next paracentesis (rev. in: [122]). Aflibercept Catumaxomab Ascites formation is also related with increased vascular permeability caused by VEGF. Aflibercept is a soluble Catumaxomab is a trifunctional rat/mouse hybrid antibody decoy receptor consisting of portions of human VEGF1 and that binds to epithelial cell adhesion molecule (EpCAM) VEGF2 receptors fused to the constant region of human present on tumor cells, to the CD3 antigen on T cells, and IgG1. It is FDA and EMA approved for the treatment of to type I, IIa, and III Fcγ receptors on accessory cells (e.g., wet macular degeneration and metastatic colorectal cancer. natural killer cells, dendritic cells, and macrophages). Catu- A randomized, double-blind, placebo-controlled, phase II maxomab exerts its anti-tumor effects via T cell-mediated trial (NCT00327444) was designed to investigate safety and lysis, antibody-dependent, cell-mediated cytotoxicity, and efficacy of IV aflibercept in inhibition of ascites formation phagocytosis via activation of FcγR-positive accessory cells in patients with advanced chemoresistant ovarian cancer. (rev. in: [124, 125]). In 2009, catumaxomab was approved by Time to next paracentesis was significantly longer in the EMA for the intraperitoneal treatment of malignant ascites experimental group (55.1 days) than in the placebo group in patients with EpCAM-positive cancer, if a standard ther- (23.3 days). There was no significant difference in over - apy is not available. A phase II study (NCT00326885) with all survival between the experimental and placebo groups IP catumaxomab in platinum-resistant ovarian cancer and [133]. The most frequent adverse events were gastrointesti- recurrent symptomatic malignant ascites showed prolonged nal disorders, dyspnea, fatigue or asthenia and dehydration. time to first therapeutic puncture and puncture-free interval, In another phase II study (NCT00396591), median time to and a beneficial effect on quality of life, with an acceptable next paracentesis was 76.0 days, which was 4.5 times longer safety profile [126]. In phase II/III trial (EudraCT 2004- than the baseline interval, before aflibercept (16.8 days). 000723-15/NCT00836654), puncture-free survival was Adverse events included hypertension, headache, anorexia, also significantly longer in the catumaxomab group than in dysphonia, and intestinal perforation (in one patient out the control group (median 46 versus 11 days; HR = 0.254; of 16 enrolled) [134]. Thus, it seems that aflibercept may p < 0.0001) as was median time to next paracentesis (77 be effective for relief the symptoms of malignant ascites, 1 3 32 Cancer Chemotherapy and Pharmacology (2018) 81:17–38 although the major limitation is related with its significant Due to its high prevalence, the majority of preclinical and morbidity (risk of bowel perforation) [133, 135]. clinical studies concern high-grade serous ovarian cancer. Other, more tailored therapies based on individual histo- logical and biological characteristics should be developed Conclusions to target less frequent histological types, such as clear cell or low-grade serous carcinoma. According to the specific Standard treatment for ovarian cancer is surgery, with a goal mutational characteristics of these subtypes, mTOR inhibi- of complete tumor resection, and chemotherapy based on tors and MEK inhibitors would apply, respectively. Better platinum compounds and taxanes. Definition of “optimal molecular and genetic characterization of different subtypes debulking” has changed over years, and now it is clear that of ovarian cancer is required, if we think about personalized survival advantage relies on complete debulking, while leav- treatment. ing any residual tumor, even < 1 cm, is related with worse So far, described biological drugs and new therapeutic prognosis. To achieve complete resection, high-quality sur- approaches were not shown to cure ovarian cancer, but they gical techniques and sophisticated equipment are required, bring the long awaited promise of turning it into a man- indicating the need for centralized treatment for ovarian can- ageable chronic disease. To bring this promise closer, price cer at specialized centers. reduction of the new drugs is awaited. Currently, there are many possible new treatment options Acknowledgements Funding was provided by Narodowe Centrum emerging from recent clinical trials, based both on the modi- Nauki (Grant no UMO-2012/04/M/NZ2/00133). fications of standard approaches and on the addition of a new biological drugs to the standard treatment. Open Access This article is distributed under the terms of the Creative Dose-dense chemotherapy is emerging as an option for Commons Attribution 4.0 International License (http://creativecom- mons.org/licenses/by/4.0/), which permits unrestricted use, distribu- patients with poor performance status. The role of IP chemo- tion, and reproduction in any medium, provided you give appropriate therapy is still not clear, as well as HIPEC. Both approaches credit to the original author(s) and the source, provide a link to the present high level of toxicity/complications and their effi- Creative Commons license, and indicate if changes were made. cacy has to be confirmed unambiguously in phase III trials. From among new drugs, bevacizumab and several PARPi were recently approved for ovarian cancer treatment. They References are still tested in several settings, including maintenance treatment which is itself an emerging approach with grow- 1. 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