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First-line treatment of ovarian cancer: questions and controversies to address

First-line treatment of ovarian cancer: questions and controversies to address 768232 TAM0010.1177/1758835918768232Therapeutic Advances in Medical OncologyJA Ledermann editorial20182018 Therapeutic Advances in Medical Oncology Editorial Ther Adv Med Oncol First-line treatment of ovarian cancer: 2018, Vol. 10: 1 –8 https://doi.org/10.1177/1758835918768232 DOI: 10.1177/ https://doi.org/10.1177/1758835918768232 questions and controversies to address © The Author(s), 2018. Reprints and permissions: http://www.sagepub.co.uk/ Jonathan A. Ledermann journalsPermissions.nav Introduction There is little doubt that the survival of women laparotomy fall into a better group responding for Correspondence to: Jonathan A. Ledermann with advanced ovarian cancer has improved over longer to chemotherapy. Progression-free survival UCL Cancer Institute, the last two decades. Platinum and paclitaxel are (PFS) differences in groups with no residual dis- Cancer Research UK and UCL Cancer Trials Centre, the two key drugs that have now been in standard ease or any residual disease are large which can 90 Tottenham Court Road, use for over 20 years. This followed the results of make interpretation of the additional value of London W1T 4TJ, UK j.ledermann@ucl.ac.uk; two large-scale trials with more than 6 years of newer systemic treatments more complex; the UCL Cancer Institute, follow up that demonstrated an 11% advantage in amount of tumour residuum has been an impor- University College London, London, UK survival with cisplatin-paclitaxel compared with tant prognostic variable and stratification factor cisplatin-cyclophosphamide, and about 40% sur- in trials. However, until recently trials were not viving 5 years. Recently, studies with carboplatin consistent, stratifying ‘good prognosis’ patients and paclitaxel, with or without bevacizumab have on the basis of less than 1 cm diameter residuum, demonstrated a median survival of almost 5 or no residual disease, which are now known to 3 5 years. A key question is what is the contribution have very different prognostic values when com- of first-line therapies to such improvements in paring different trials. While the eradication of survival? To what extent is the improvement due microscopic disease may be easier in this group, to the drugs used in first-line treatment, the ben- the eventual outcome of patients will depend efit of better surgery, multidisciplinary care, or upon the quality of the systemic treatment that the contribution of drug therapies post-progres- follows. Such treatment still needs to improve if it sion? To understand this better, it is important to is to significantly increase the long-term survival examine the time to failure of first-line treatment, of patients post-surgery. namely progression-free survival. For many years the strategy to improve first-line A decade of trials in first-line therapy treatment was centred around using better chem- First-line chemotherapy with carboplatin and otherapy drugs and improving the quality of sur- paclitaxel became the standard chemotherapy 7–9 gery. Meticulous analysis of surgical effort, either combination more than 20 years ago, and is through case series or within the context of ran- the yardstick against which newer treatments are 5,6 domized clinical trials of chemotherapy has now evaluated. In the late 1900s there was inter- shown that tumour cytoreduction to microscopic est in using very high doses of chemotherapy in residual disease confers a better outcome. solid tumours, or multiple sequential drug thera- However, surgical effort alone may not be the pies. Trials using these approaches, published only factor. In the large multicentre Gynecologic almost a decade ago showed that these strategies Oncology Group (GOG) 182 trial, disease bur- did not significantly extend the PFS following 10,11 den and the extent of disease distribution also first-line therapy. As ovarian cancer is usually affected outcome, independent of cytoreduction confined to the peritoneal cavity there has also to no macroscopic residual disease. The argu- been a long-standing interest in intraperitoneal ment that biology leading to easier debulking therapy. Over 20 years, this therapeutic approach rather than surgical effort is responsible for a bet- has divided the oncology community into ‘believ- ter survival is weakening. Centralized (special- ers’ and ‘doubters’ and intraperitoneal therapy ized) care and data from within randomized trials continues to stimulate debate, without gaining point to surgical effort as being an independent widespread acceptance. For all the criticism that predictor of survival. Thus, more patients under- has been levied, the historical trials have shown going complete removal of disease at primary some benefit for intraperitoneal therapy and journals.sagepub.com/home/tam 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology 10 none has shown any disadvantage in outcome. The second systemic approach has been to incor- However, PFS remains largely similar to systemic porate the anti-angiogenic drug, bevacizumab chemotherapy trials, although case selection, into first-line treatment. The results of two key particularly the degree of surgical debulking con- first-line trials, GOG 218 and ICON 7 were pub- 19,20 tinues to confound interpretation of this lished in 2011. The key finding in the GOG approach. While the long-term outcome of trial was that bevacizumab, 15 mg/kg 3-weekly, patients with microscopic residual disease, as given with chemotherapy and for up to 15 months seen in GOG 172 continues to show a survival significantly prolonged the time to disease pro- benefit with 10 years of follow up the most gression compared with placebo. There was no recently conducted study, as yet not fully pub- difference in OS. Without debating the cost- lished, failed to show any difference in PFS effectiveness of a difference of 3.8 months in between the intravenous and intraperitoneal median PFS, the attitude to the results in Europe arms. Modification of the technique using and the USA differed. Submission to the hyperthermic infusion of drugs (HIPEC) has European Medicines Agency (EMA) led to regu- reported a benefit in PFS in the experimental latory approval but the results were not consid- arm. However, the median PFS was similar to ered sufficiently compelling to submit to the US that seen in multiple other trials over the last dec- Food and Drug Administration (FDA). As a con- ade. Nevertheless, the trial reported significant sequence, there has been a divergence in the differences in survival which cannot easily be ‘standard of care’ of first-line systemic treatment explained. The result continues to stimulate across the two sides of the Atlantic. Bevacizumab debate and the hypothesis that there may be has become a standard option in Europe and this something unusual about intraperitoneal ther- has shaped the development of new trials that apy, with differences in overall survival (OS) vis- incorporate this standard of care. The largest dif- ible several years later. Most of the clinical ference in PFS for both ICON 7, using half the research in first-line systemic therapy over the dose of bevacizumab and for a shorter duration last decade has followed two directions. One, a (12 months rather than 15 months for GOG 218) simple approach of dose scheduling paclitaxel, occurred at the time treatment stopped. Thus, it using a weekly rather than a 3-weekly schedule. has been hypothesized that a greater benefit The results of a randomized trial from a Japanese (increase in median PFS difference) might be trial (JGOG 3016) suggested that this approach achieved by giving bevacizumab for longer. This could significantly improve outcome, both by is being tested in the ‘Boost’ trial [ClinicalTrials. prolonging the PFS and OS. The magnitude of gov identifier: NCT01462890; AGO-OVAR 17] benefit reported was substantially greater than comparing 15 with 30 months treatment with had been seen in any other first-line trial for more bevacizumab. More than 900 women have been than a decade, and this led to a major interna- recruited to this study and the results are eagerly tional effort to confirm the results. The two large awaited. However, one might also consider the trials from the United States of America (USA) possibility that the maximum differences in PFS (GOG 262) and Italy (MITO 7), neither occurred coincidentally at the time bevacizumab exactly replicating the experimental question was stopped. In the GOG 262 trial bevacizumab, addressed in the Japanese trial, failed to confirm which was given by choice to 84% of the patients 16,17 a benefit of weekly paclitaxel. However, criti- was continued until progression/toxicity and the cisms of these two studies, one of which allowed median PFS was about 15 months, not very dif- the addition of bevacizumab in 85% of the ferent from the bevacizumab-throughout group 16,19 patients and the other that used a lower dose of in GOG 218. Currently, cost, and to a lesser weekly paclitaxel and also weekly carboplatin, led extent toxicity, has led to many countries to adopt many to adopt weekly paclitaxel as a standard of the lower dose of bevacizumab and shorter dura- care. The results of a third trial, ICON8, the tion of therapy, as used in the ICON7 trial. This largest of the confirmatory studies, was presented choice, using the drug ‘off-label’ has been rein- at the European Society for Medical Oncology forced by a subgroup post hoc analysis showing (ESMO) 2017 Congress. This was a three-arm that patients predicted to have a ‘poorer progno- study that included the ‘Japanese’ regimen as sis’ (stage III with >1 cm residual disease, or well as an arm with weekly carboplatin and stage IV), had the greatest benefit from bevaci- weekly paclitaxel. None of the experimental arms zumab; the median PFS difference in this sub- showed any difference in PFS compared with group was 6.5 months, and in this subgroup 18 21 standard 3-weekly paclitaxel. there was an OS benefit. The demographics of 2 journals.sagepub.com/home/tam JA Ledermann the patients entered into GOG 218 and ICON 7 treatments and in some situations, cross over to were slightly different, but in a retrospective anal- the experimental therapy. This is exemplified by ysis no difference in survival was seen in patients the trial of maintenance olaparib therapy in with a similar prediction of a poorer prognosis; it platinum-sensitive recurrent ovarian cancer was only in the stage IV subset of GOG 2018 that (study 19) which led to very large differences in an OS benefit was seen, but these results are not PFS but much smaller differences in OS. An fully published. exploratory analysis removing patients (and cen- tres) where crossover occurred showed a signifi- Not surprisingly, efforts to demonstrate the value cant difference in OS with maintenance olaparib. of anti-angiogenic drugs in first-line therapy have Additionally, because of a long post-progression been explored further, using oral inhibitors of survival, OS results often become available vascular endothelial growth factor (VEGF) recep- several years after recruitment to the trial is tor tyrosine kinase. However, neither of the two completed. As there is both a commercial and, to large trials with 2 years of pazopanib maintenance some extent, academic pressure to analyze results therapy or nintedanib with chemotherapy and as early, PFS has become a primary endpoint for maintenance for a total of 24 months have dem- many first-line trials. Important secondary end- onstrated sufficient differences in median PFS to points can be used to support improvements in lead to applications for a licence to the regulatory the PFS result, without waiting for OS data, and 23,24 authorities. Bevacizumab is now the most the uncertainty about whether a difference will consistently used additional drug in the first-line emerge. The relevance of these secondary end- treatment of ovarian cancer, and several years points becomes even more important if the differ- after publication of the results, it is now being ence in PFS is relatively small, and unlikely to considered by the US FDA as an option for first- lead to an OS difference. An exploratory second- line therapy in the USA (https://www.gene.com/ ary endpoint, such as the time to subsequent pro- media/press-releases/14685/2017-10-25/fda- gression (after the next line of therapy), also accepts-genentechs-supplemental-biol). Table 1 known as PFS2, indirectly determined as the summarizes the results of a number of strategies TSST (time to second subsequent treatment) used to improve the results of first-line treatment was measured in study 19, due to the absence of over the last 18 years. While inter-trial compari- an OS difference. This endpoint has some value, sons should be made with caution due to differ- given the difficulties in demonstrating OS differ- ences in prognostic variables, particularly the ences. However, like OS PFS2 may be influenced amount of residual disease, the median PFS for by the timing of further treatment in the two arms 3-weekly carboplatin and paclitaxel within these as well as differences in the subsequent treatment. studies is remarkably consistent and there has Nevertheless, a sustained differences in PFS2 been little advance in time to failure of first-line shows that the benefit of an investigational drug chemotherapy in the various intravenous chemo- continues after progression, at least to a sub- therapy strategies employed over the last two sequent progression. This supplementary end- decades. point, demonstrated prospectively in the SOLO-2 trial of maintenance olaparib, is acceptable to the EMA as a coregulatory endpoint to a PFS dif- Current trials and evaluation of first-line ference in situations where in the significant OS therapies differences are not demonstrated, or have not had Before reviewing ongoing clinical trials and future sufficient time to mature. While these endpoints strategies, it is worthwhile reflecting on how became established in trials of recurrent ovarian improvements in first-line therapy are measured cancer, similar considerations are now being and evaluated. While the aim is to develop treat- applied to first-line therapy trials, with recom- ments that increase OS these are difficult to dem- mendations following the Fifth Ovarian Cancer onstrate. The ideal scenario is to develop a Consensus Conference (OCCC) of the Gynecologic treatment that would demonstrate a significant Cancer InterGroup that in situations where OS is benefit in PFS during first-line treatment and the not the primary endpoint, PFS2 or quality of life difference between treatments would continue to should be used to support differences in PFS. be upheld during subsequent treatments, leading ultimately to a difference in OS. This is rarely For comparisons of new cytotoxic chemotherapy, seen, partly because of the long post-progression one could argue that PFS is the most important survival in ovarian cancer, with multiple subsequent endpoint. In the absence of a demonstration of journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology 10 Table 1. Two decades of first-line chemotherapy trials in ovarian cancer. Trial question Details Median PFS Median PFS Comments (months) (months) carboplatin/ experimental paclitaxel Carboplatin/paclitaxel versus cisplatin/paclitaxel Neijt and colleagues Cisplatin-paclitaxel standard 16.0 16 44% <1 cm residual disease (2000) Ozols and colleagues Cisplatin-paclitaxel standard 20.7 19.4 36% no macroscopic residual (2003) disease. Large difference in PFS depending on residual disease Du Bois and colleagues Cisplatin-paclitaxel standard 17.2 19.1 60% <1 cm residual disease (2003) Three drugs/ sequential doublets Du Bois and colleagues Epirubicin 17.9 18.4 58% <1 cm residual disease/ (2006) lower stage Bookman and GOG 182/ICON5 8 cycles, 16.0 16.0 Median PFS 12–130 months colleagues (2009) 5-arm study (topotecan, depending on residual disease gemcitabine, PLD) sequential doublet/triplet Gemcitabine 19.3 17.8 70% <1 cm residual disease HD chemotherapy with peripheral blood stem cell rescue Moebus and colleagues 3 cycles HD chemotherapy 20.5 29.6 35% no macroscopic residual (2010) including HD melphalan disease Inclusion of anti-angiogenic drugs followed by maintenance Burger and colleagues GOG 218- bevacizumab 12.0 18.0 33% <1 cm residual disease (2011) 15 months Perren and colleagues ICON7- bevacizumab 17.3 19.0 24% microscopic residual (2011) 12 months disease Du Bois and colleagues OVAR12- nintedanib 16.6 17.2 41% No macroscopic residual (2016) 24 months disease Dose-dense (weekly) paclitaxel Katsumata and JGOG 3016 17.2 28.0 45% <1 cm residual disease colleagues (2009) Pignata and colleagues MITO7- weekly carboplatin 17.3 18.3 41% no macroscopic residual (2014) and paclitaxel disease Chan and colleagues GOG 262- 85% with 14.0 14.7 24% microscopic residual (2016) bevacizumab disease GOG, Gynecologic Oncology Group; HD, high dose; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin. superiority, it is unlikely that a new treatment eradicates malignant cells. It acts by delaying is going to be more effective. The two trials growth through interference with the tumour vas- with bevacizumab fit into this group. However, culature as long as it is given. This notion is sup- it is reasonable to regard bevacizumab as a ported by the effect of the drug being greatest at disease-modifying agent, rather than a drug that the time it is stopped. One could argue that the 4 journals.sagepub.com/home/tam JA Ledermann apparent survival benefit in the poorer prognosis [ClinicalTrials.gov identifier: NCT02477644]. subgroup of ICON7 is due to patients being on The hypothesis is that bevacizumab increases the the drug longer, surviving in a better clinical state activity of the PARP inhibitor, perhaps by increas- to receive subsequent treatment, rather than a ing the degree of homologous recombination direct effect of the drug per se. Thus, while the deficiency in the tumour thereby increasing the results of AGO-OVAR17 are awaited, it may turn PFS due to bevacizumab. Clinical data combin- out that prolongation of bevacizumab therapy for ing the VEGF receptor inhibitor, cediranib and 30 months will further extenuate differences in olaparib support this approach. In a subgroup PFS without showing a survival difference. The analysis the greatest benefit of combining interpretation, or evaluation of measured differ- cediranib and olaparib was seen in the non- ences in PFS is complex, and the extent to which germline BRCA mutation group/BRCA wildtype. these translate into a ‘healthcare benefit’ is beyond In PAOLA-1 which includes patients irrespective the scope of this review. Arguments continue of BRCA status, bevacizumab continues for 15 about the relative merits of small differences in months in combination with the trial drug, that is PFS after first-line therapy and the delay in sec- then given for a further 9 months on its own. ond-line therapy in the context of little or no ben- efit in OS. For the future design of trials, the Fifth Special considerations are needed when inter- OCCC concluded that differences in PFS are preting the effect of immunotherapy studies. This valuable as a primary endpoint, but trials should is a very different strategy from cytotoxic chemo- be followed to measure OS. Thus, trials should therapy that that relies on the development of a be powered to show differences in PFS and be of host immune response. Significant therapeutic sufficient size to allow a robust analysis of second- benefit has been seen using inhibitors of immune ary endpoints. checkpoints that stimulate a host anti-tumour response and prolong survival in many types of The next group of trials to report are examining solid tumour. Of note, such effects may occur the inclusion of poly ADP ribose polymerase well beyond the time of therapy; having engaged (PARP) inhibitors. These drugs have shown clear the host immune system, differences in outcome benefit in recurrent ovarian cancer, and mainte- may occur after progression. There are examples nance therapy is now being evaluated in first-line from other diseases where differences in OS have therapy. The results of four important trials are emerged without any major difference in PFS. awaited. The first trial, SOLO-1 using mainte- nance olaparib or placebo for 2 years in women with a BRCA mutation who have responded to Future prospects for first-line treatment first-line therapy has been completed. The results While awaiting these important results, clinical are expected within the next year or so. It is trial development in ovarian cancer, led by indus- expected that PFS will be extended, as only try, is moving rapidly and new studies are being patients responding to chemotherapy are rand- designed to evaluate immune checkpoint inhibi- omized to maintenance therapy, but the impor- tors in ovarian cancer. The impetus comes from tance of this study is whether time-limited the results of treatment in other solid tumours olaparib therapy significantly improves OS, or such as lung, bladder, and head and neck cancers. just delays progression without influencing OS. To date, the only full publication of the effect of The second study, GOG 3005 which has com- immune checkpoint inhibitors in ovarian cancer pleted accrual is targeting the concomitant and is in recurrent disease and reports the activity of maintenance use of veliparib in the primary setting the programmed death-ligand 1 (PDL1) inhibi- [ClinicalTrials.gov identifier: NCT02470585]. The tor, nivolumab in a small number of patients; third, PRIMA trial [ClinicalTrials.gov identifier: other information is only available as published NCT02655016] is an ongoing study of mainte- abstracts. Notwithstanding the paucity of pub- nance niraparib or placebo following therapy of lished data, more than 900 patients have been patients with suboptimal stage III or stage IV dis- enrolled in the first-line study, JAVELIN 100 ease following surgery and chemotherapy. It [ClinicalTrials.gov identifier: NCT02718417] includes a broader group of women including with the PDL1 inhibitor avelumab. The trial those without a BRCA mutation. The fourth closed to recruitment in January 2018. Patients study, PAOLA-1 is a little different as it is evalu- will receive avelumab for up to 2 years or to ating the addition of olaparib or placebo mainte- progression, so the results will not be available nance to bevacizumab following first-line therapy for some while. A second trial, IMaGYN050 journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology 10 4. Bristow RE, Tomacruz RS, Armstrong DK, et al. [ClinicalTrials.gov identifier: NCT03038100] Survival effect of maximal cytoreductive surgery using bevacizumab and atezolizumab, a PDL1 for advanced ovarian carcinoma during the inhibitor is underway. For JAVELIN 100, PFS is platinum era: a meta-analysis. J Clin Oncol 2002; the primary endpoint, but it is vital that follow up 20: 1248–1259. is continued to assess OS, the secondary end- point. For IMaGYN050, PFS and OS are co- 5. du Bois A, Reuss A, Pujade-Lauraine E, et al. 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First-line treatment of ovarian cancer: questions and controversies to address

Therapeutic Advances in Medical Oncology , Volume 10 – Apr 11, 2018

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768232 TAM0010.1177/1758835918768232Therapeutic Advances in Medical OncologyJA Ledermann editorial20182018 Therapeutic Advances in Medical Oncology Editorial Ther Adv Med Oncol First-line treatment of ovarian cancer: 2018, Vol. 10: 1 –8 https://doi.org/10.1177/1758835918768232 DOI: 10.1177/ https://doi.org/10.1177/1758835918768232 questions and controversies to address © The Author(s), 2018. Reprints and permissions: http://www.sagepub.co.uk/ Jonathan A. Ledermann journalsPermissions.nav Introduction There is little doubt that the survival of women laparotomy fall into a better group responding for Correspondence to: Jonathan A. Ledermann with advanced ovarian cancer has improved over longer to chemotherapy. Progression-free survival UCL Cancer Institute, the last two decades. Platinum and paclitaxel are (PFS) differences in groups with no residual dis- Cancer Research UK and UCL Cancer Trials Centre, the two key drugs that have now been in standard ease or any residual disease are large which can 90 Tottenham Court Road, use for over 20 years. This followed the results of make interpretation of the additional value of London W1T 4TJ, UK j.ledermann@ucl.ac.uk; two large-scale trials with more than 6 years of newer systemic treatments more complex; the UCL Cancer Institute, follow up that demonstrated an 11% advantage in amount of tumour residuum has been an impor- University College London, London, UK survival with cisplatin-paclitaxel compared with tant prognostic variable and stratification factor cisplatin-cyclophosphamide, and about 40% sur- in trials. However, until recently trials were not viving 5 years. Recently, studies with carboplatin consistent, stratifying ‘good prognosis’ patients and paclitaxel, with or without bevacizumab have on the basis of less than 1 cm diameter residuum, demonstrated a median survival of almost 5 or no residual disease, which are now known to 3 5 years. A key question is what is the contribution have very different prognostic values when com- of first-line therapies to such improvements in paring different trials. While the eradication of survival? To what extent is the improvement due microscopic disease may be easier in this group, to the drugs used in first-line treatment, the ben- the eventual outcome of patients will depend efit of better surgery, multidisciplinary care, or upon the quality of the systemic treatment that the contribution of drug therapies post-progres- follows. Such treatment still needs to improve if it sion? To understand this better, it is important to is to significantly increase the long-term survival examine the time to failure of first-line treatment, of patients post-surgery. namely progression-free survival. For many years the strategy to improve first-line A decade of trials in first-line therapy treatment was centred around using better chem- First-line chemotherapy with carboplatin and otherapy drugs and improving the quality of sur- paclitaxel became the standard chemotherapy 7–9 gery. Meticulous analysis of surgical effort, either combination more than 20 years ago, and is through case series or within the context of ran- the yardstick against which newer treatments are 5,6 domized clinical trials of chemotherapy has now evaluated. In the late 1900s there was inter- shown that tumour cytoreduction to microscopic est in using very high doses of chemotherapy in residual disease confers a better outcome. solid tumours, or multiple sequential drug thera- However, surgical effort alone may not be the pies. Trials using these approaches, published only factor. In the large multicentre Gynecologic almost a decade ago showed that these strategies Oncology Group (GOG) 182 trial, disease bur- did not significantly extend the PFS following 10,11 den and the extent of disease distribution also first-line therapy. As ovarian cancer is usually affected outcome, independent of cytoreduction confined to the peritoneal cavity there has also to no macroscopic residual disease. The argu- been a long-standing interest in intraperitoneal ment that biology leading to easier debulking therapy. Over 20 years, this therapeutic approach rather than surgical effort is responsible for a bet- has divided the oncology community into ‘believ- ter survival is weakening. Centralized (special- ers’ and ‘doubters’ and intraperitoneal therapy ized) care and data from within randomized trials continues to stimulate debate, without gaining point to surgical effort as being an independent widespread acceptance. For all the criticism that predictor of survival. Thus, more patients under- has been levied, the historical trials have shown going complete removal of disease at primary some benefit for intraperitoneal therapy and journals.sagepub.com/home/tam 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology 10 none has shown any disadvantage in outcome. The second systemic approach has been to incor- However, PFS remains largely similar to systemic porate the anti-angiogenic drug, bevacizumab chemotherapy trials, although case selection, into first-line treatment. The results of two key particularly the degree of surgical debulking con- first-line trials, GOG 218 and ICON 7 were pub- 19,20 tinues to confound interpretation of this lished in 2011. The key finding in the GOG approach. While the long-term outcome of trial was that bevacizumab, 15 mg/kg 3-weekly, patients with microscopic residual disease, as given with chemotherapy and for up to 15 months seen in GOG 172 continues to show a survival significantly prolonged the time to disease pro- benefit with 10 years of follow up the most gression compared with placebo. There was no recently conducted study, as yet not fully pub- difference in OS. Without debating the cost- lished, failed to show any difference in PFS effectiveness of a difference of 3.8 months in between the intravenous and intraperitoneal median PFS, the attitude to the results in Europe arms. Modification of the technique using and the USA differed. Submission to the hyperthermic infusion of drugs (HIPEC) has European Medicines Agency (EMA) led to regu- reported a benefit in PFS in the experimental latory approval but the results were not consid- arm. However, the median PFS was similar to ered sufficiently compelling to submit to the US that seen in multiple other trials over the last dec- Food and Drug Administration (FDA). As a con- ade. Nevertheless, the trial reported significant sequence, there has been a divergence in the differences in survival which cannot easily be ‘standard of care’ of first-line systemic treatment explained. The result continues to stimulate across the two sides of the Atlantic. Bevacizumab debate and the hypothesis that there may be has become a standard option in Europe and this something unusual about intraperitoneal ther- has shaped the development of new trials that apy, with differences in overall survival (OS) vis- incorporate this standard of care. The largest dif- ible several years later. Most of the clinical ference in PFS for both ICON 7, using half the research in first-line systemic therapy over the dose of bevacizumab and for a shorter duration last decade has followed two directions. One, a (12 months rather than 15 months for GOG 218) simple approach of dose scheduling paclitaxel, occurred at the time treatment stopped. Thus, it using a weekly rather than a 3-weekly schedule. has been hypothesized that a greater benefit The results of a randomized trial from a Japanese (increase in median PFS difference) might be trial (JGOG 3016) suggested that this approach achieved by giving bevacizumab for longer. This could significantly improve outcome, both by is being tested in the ‘Boost’ trial [ClinicalTrials. prolonging the PFS and OS. The magnitude of gov identifier: NCT01462890; AGO-OVAR 17] benefit reported was substantially greater than comparing 15 with 30 months treatment with had been seen in any other first-line trial for more bevacizumab. More than 900 women have been than a decade, and this led to a major interna- recruited to this study and the results are eagerly tional effort to confirm the results. The two large awaited. However, one might also consider the trials from the United States of America (USA) possibility that the maximum differences in PFS (GOG 262) and Italy (MITO 7), neither occurred coincidentally at the time bevacizumab exactly replicating the experimental question was stopped. In the GOG 262 trial bevacizumab, addressed in the Japanese trial, failed to confirm which was given by choice to 84% of the patients 16,17 a benefit of weekly paclitaxel. However, criti- was continued until progression/toxicity and the cisms of these two studies, one of which allowed median PFS was about 15 months, not very dif- the addition of bevacizumab in 85% of the ferent from the bevacizumab-throughout group 16,19 patients and the other that used a lower dose of in GOG 218. Currently, cost, and to a lesser weekly paclitaxel and also weekly carboplatin, led extent toxicity, has led to many countries to adopt many to adopt weekly paclitaxel as a standard of the lower dose of bevacizumab and shorter dura- care. The results of a third trial, ICON8, the tion of therapy, as used in the ICON7 trial. This largest of the confirmatory studies, was presented choice, using the drug ‘off-label’ has been rein- at the European Society for Medical Oncology forced by a subgroup post hoc analysis showing (ESMO) 2017 Congress. This was a three-arm that patients predicted to have a ‘poorer progno- study that included the ‘Japanese’ regimen as sis’ (stage III with >1 cm residual disease, or well as an arm with weekly carboplatin and stage IV), had the greatest benefit from bevaci- weekly paclitaxel. None of the experimental arms zumab; the median PFS difference in this sub- showed any difference in PFS compared with group was 6.5 months, and in this subgroup 18 21 standard 3-weekly paclitaxel. there was an OS benefit. The demographics of 2 journals.sagepub.com/home/tam JA Ledermann the patients entered into GOG 218 and ICON 7 treatments and in some situations, cross over to were slightly different, but in a retrospective anal- the experimental therapy. This is exemplified by ysis no difference in survival was seen in patients the trial of maintenance olaparib therapy in with a similar prediction of a poorer prognosis; it platinum-sensitive recurrent ovarian cancer was only in the stage IV subset of GOG 2018 that (study 19) which led to very large differences in an OS benefit was seen, but these results are not PFS but much smaller differences in OS. An fully published. exploratory analysis removing patients (and cen- tres) where crossover occurred showed a signifi- Not surprisingly, efforts to demonstrate the value cant difference in OS with maintenance olaparib. of anti-angiogenic drugs in first-line therapy have Additionally, because of a long post-progression been explored further, using oral inhibitors of survival, OS results often become available vascular endothelial growth factor (VEGF) recep- several years after recruitment to the trial is tor tyrosine kinase. However, neither of the two completed. As there is both a commercial and, to large trials with 2 years of pazopanib maintenance some extent, academic pressure to analyze results therapy or nintedanib with chemotherapy and as early, PFS has become a primary endpoint for maintenance for a total of 24 months have dem- many first-line trials. Important secondary end- onstrated sufficient differences in median PFS to points can be used to support improvements in lead to applications for a licence to the regulatory the PFS result, without waiting for OS data, and 23,24 authorities. Bevacizumab is now the most the uncertainty about whether a difference will consistently used additional drug in the first-line emerge. The relevance of these secondary end- treatment of ovarian cancer, and several years points becomes even more important if the differ- after publication of the results, it is now being ence in PFS is relatively small, and unlikely to considered by the US FDA as an option for first- lead to an OS difference. An exploratory second- line therapy in the USA (https://www.gene.com/ ary endpoint, such as the time to subsequent pro- media/press-releases/14685/2017-10-25/fda- gression (after the next line of therapy), also accepts-genentechs-supplemental-biol). Table 1 known as PFS2, indirectly determined as the summarizes the results of a number of strategies TSST (time to second subsequent treatment) used to improve the results of first-line treatment was measured in study 19, due to the absence of over the last 18 years. While inter-trial compari- an OS difference. This endpoint has some value, sons should be made with caution due to differ- given the difficulties in demonstrating OS differ- ences in prognostic variables, particularly the ences. However, like OS PFS2 may be influenced amount of residual disease, the median PFS for by the timing of further treatment in the two arms 3-weekly carboplatin and paclitaxel within these as well as differences in the subsequent treatment. studies is remarkably consistent and there has Nevertheless, a sustained differences in PFS2 been little advance in time to failure of first-line shows that the benefit of an investigational drug chemotherapy in the various intravenous chemo- continues after progression, at least to a sub- therapy strategies employed over the last two sequent progression. This supplementary end- decades. point, demonstrated prospectively in the SOLO-2 trial of maintenance olaparib, is acceptable to the EMA as a coregulatory endpoint to a PFS dif- Current trials and evaluation of first-line ference in situations where in the significant OS therapies differences are not demonstrated, or have not had Before reviewing ongoing clinical trials and future sufficient time to mature. While these endpoints strategies, it is worthwhile reflecting on how became established in trials of recurrent ovarian improvements in first-line therapy are measured cancer, similar considerations are now being and evaluated. While the aim is to develop treat- applied to first-line therapy trials, with recom- ments that increase OS these are difficult to dem- mendations following the Fifth Ovarian Cancer onstrate. The ideal scenario is to develop a Consensus Conference (OCCC) of the Gynecologic treatment that would demonstrate a significant Cancer InterGroup that in situations where OS is benefit in PFS during first-line treatment and the not the primary endpoint, PFS2 or quality of life difference between treatments would continue to should be used to support differences in PFS. be upheld during subsequent treatments, leading ultimately to a difference in OS. This is rarely For comparisons of new cytotoxic chemotherapy, seen, partly because of the long post-progression one could argue that PFS is the most important survival in ovarian cancer, with multiple subsequent endpoint. In the absence of a demonstration of journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology 10 Table 1. Two decades of first-line chemotherapy trials in ovarian cancer. Trial question Details Median PFS Median PFS Comments (months) (months) carboplatin/ experimental paclitaxel Carboplatin/paclitaxel versus cisplatin/paclitaxel Neijt and colleagues Cisplatin-paclitaxel standard 16.0 16 44% <1 cm residual disease (2000) Ozols and colleagues Cisplatin-paclitaxel standard 20.7 19.4 36% no macroscopic residual (2003) disease. Large difference in PFS depending on residual disease Du Bois and colleagues Cisplatin-paclitaxel standard 17.2 19.1 60% <1 cm residual disease (2003) Three drugs/ sequential doublets Du Bois and colleagues Epirubicin 17.9 18.4 58% <1 cm residual disease/ (2006) lower stage Bookman and GOG 182/ICON5 8 cycles, 16.0 16.0 Median PFS 12–130 months colleagues (2009) 5-arm study (topotecan, depending on residual disease gemcitabine, PLD) sequential doublet/triplet Gemcitabine 19.3 17.8 70% <1 cm residual disease HD chemotherapy with peripheral blood stem cell rescue Moebus and colleagues 3 cycles HD chemotherapy 20.5 29.6 35% no macroscopic residual (2010) including HD melphalan disease Inclusion of anti-angiogenic drugs followed by maintenance Burger and colleagues GOG 218- bevacizumab 12.0 18.0 33% <1 cm residual disease (2011) 15 months Perren and colleagues ICON7- bevacizumab 17.3 19.0 24% microscopic residual (2011) 12 months disease Du Bois and colleagues OVAR12- nintedanib 16.6 17.2 41% No macroscopic residual (2016) 24 months disease Dose-dense (weekly) paclitaxel Katsumata and JGOG 3016 17.2 28.0 45% <1 cm residual disease colleagues (2009) Pignata and colleagues MITO7- weekly carboplatin 17.3 18.3 41% no macroscopic residual (2014) and paclitaxel disease Chan and colleagues GOG 262- 85% with 14.0 14.7 24% microscopic residual (2016) bevacizumab disease GOG, Gynecologic Oncology Group; HD, high dose; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin. superiority, it is unlikely that a new treatment eradicates malignant cells. It acts by delaying is going to be more effective. The two trials growth through interference with the tumour vas- with bevacizumab fit into this group. However, culature as long as it is given. This notion is sup- it is reasonable to regard bevacizumab as a ported by the effect of the drug being greatest at disease-modifying agent, rather than a drug that the time it is stopped. One could argue that the 4 journals.sagepub.com/home/tam JA Ledermann apparent survival benefit in the poorer prognosis [ClinicalTrials.gov identifier: NCT02477644]. subgroup of ICON7 is due to patients being on The hypothesis is that bevacizumab increases the the drug longer, surviving in a better clinical state activity of the PARP inhibitor, perhaps by increas- to receive subsequent treatment, rather than a ing the degree of homologous recombination direct effect of the drug per se. Thus, while the deficiency in the tumour thereby increasing the results of AGO-OVAR17 are awaited, it may turn PFS due to bevacizumab. Clinical data combin- out that prolongation of bevacizumab therapy for ing the VEGF receptor inhibitor, cediranib and 30 months will further extenuate differences in olaparib support this approach. In a subgroup PFS without showing a survival difference. The analysis the greatest benefit of combining interpretation, or evaluation of measured differ- cediranib and olaparib was seen in the non- ences in PFS is complex, and the extent to which germline BRCA mutation group/BRCA wildtype. these translate into a ‘healthcare benefit’ is beyond In PAOLA-1 which includes patients irrespective the scope of this review. Arguments continue of BRCA status, bevacizumab continues for 15 about the relative merits of small differences in months in combination with the trial drug, that is PFS after first-line therapy and the delay in sec- then given for a further 9 months on its own. ond-line therapy in the context of little or no ben- efit in OS. For the future design of trials, the Fifth Special considerations are needed when inter- OCCC concluded that differences in PFS are preting the effect of immunotherapy studies. This valuable as a primary endpoint, but trials should is a very different strategy from cytotoxic chemo- be followed to measure OS. Thus, trials should therapy that that relies on the development of a be powered to show differences in PFS and be of host immune response. Significant therapeutic sufficient size to allow a robust analysis of second- benefit has been seen using inhibitors of immune ary endpoints. checkpoints that stimulate a host anti-tumour response and prolong survival in many types of The next group of trials to report are examining solid tumour. Of note, such effects may occur the inclusion of poly ADP ribose polymerase well beyond the time of therapy; having engaged (PARP) inhibitors. These drugs have shown clear the host immune system, differences in outcome benefit in recurrent ovarian cancer, and mainte- may occur after progression. There are examples nance therapy is now being evaluated in first-line from other diseases where differences in OS have therapy. The results of four important trials are emerged without any major difference in PFS. awaited. The first trial, SOLO-1 using mainte- nance olaparib or placebo for 2 years in women with a BRCA mutation who have responded to Future prospects for first-line treatment first-line therapy has been completed. The results While awaiting these important results, clinical are expected within the next year or so. It is trial development in ovarian cancer, led by indus- expected that PFS will be extended, as only try, is moving rapidly and new studies are being patients responding to chemotherapy are rand- designed to evaluate immune checkpoint inhibi- omized to maintenance therapy, but the impor- tors in ovarian cancer. The impetus comes from tance of this study is whether time-limited the results of treatment in other solid tumours olaparib therapy significantly improves OS, or such as lung, bladder, and head and neck cancers. just delays progression without influencing OS. To date, the only full publication of the effect of The second study, GOG 3005 which has com- immune checkpoint inhibitors in ovarian cancer pleted accrual is targeting the concomitant and is in recurrent disease and reports the activity of maintenance use of veliparib in the primary setting the programmed death-ligand 1 (PDL1) inhibi- [ClinicalTrials.gov identifier: NCT02470585]. The tor, nivolumab in a small number of patients; third, PRIMA trial [ClinicalTrials.gov identifier: other information is only available as published NCT02655016] is an ongoing study of mainte- abstracts. Notwithstanding the paucity of pub- nance niraparib or placebo following therapy of lished data, more than 900 patients have been patients with suboptimal stage III or stage IV dis- enrolled in the first-line study, JAVELIN 100 ease following surgery and chemotherapy. It [ClinicalTrials.gov identifier: NCT02718417] includes a broader group of women including with the PDL1 inhibitor avelumab. The trial those without a BRCA mutation. The fourth closed to recruitment in January 2018. Patients study, PAOLA-1 is a little different as it is evalu- will receive avelumab for up to 2 years or to ating the addition of olaparib or placebo mainte- progression, so the results will not be available nance to bevacizumab following first-line therapy for some while. A second trial, IMaGYN050 journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology 10 4. Bristow RE, Tomacruz RS, Armstrong DK, et al. [ClinicalTrials.gov identifier: NCT03038100] Survival effect of maximal cytoreductive surgery using bevacizumab and atezolizumab, a PDL1 for advanced ovarian carcinoma during the inhibitor is underway. For JAVELIN 100, PFS is platinum era: a meta-analysis. J Clin Oncol 2002; the primary endpoint, but it is vital that follow up 20: 1248–1259. is continued to assess OS, the secondary end- point. For IMaGYN050, PFS and OS are co- 5. du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic primary endpoints. The rapid enrolment seen in factor in advanced epithelial ovarian cancer: a these studies is a reflection of the urgent need per- combined exploratory analysis of 3 prospectively ceived by doctors and their patients to find a new randomized phase 3 multicenter trials: by the treatment leading to a step-change in the man- Arbeitsgemeinschaft Gynaekologische Onkologie agement of ovarian cancer. The first tranche of Studiengruppe Ovarialkarzinom (AGO-OVAR) results using PARP inhibitors may herald such a and the Groupe d’Investigateurs Nationaux Pour change, but we will need to wait several more les Etudes des Cancers de l’Ovaire (GINECO). years before any conclusions can be drawn about Cancer 2009; 115: 1234–1244. the role of immune checkpoint inhibitors. While 6. Horowitz NS, Miller A, Rungruang B, et al. Does patients are living longer, it is hard currently to aggressive surgery improve outcomes? 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Published: Apr 11, 2018

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