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Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive,... www.nature.com/bjc ARTICLE Clinical Study Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy 1 2 3 4 5 6 7 Michael Friedlander , Ursula Matulonis , Charlie Gourley , Andreas du Bois , Ignace Vergote , Gordon Rustin , Clare Scott , 8 9 10,11 12 13 14,15 16,19 Werner Meier , Ronnie Shapira-Frommer , Tamar Safra , Daniela Matei , Vadim Shirinkin , Frédéric Selle , Anitra Fielding , 17 16 16 16 16 16 18 Elizabeth S. Lowe , Emma L. McMurtry , Stuart Spencer , Philip Rowe , Helen Mann , David Parry and Jonathan Ledermann BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long- term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients. British Journal of Cancer (2018) 119:1075–1085; https://doi.org/10.1038/s41416-018-0271-y INTRODUCTION delivery and potential benefit of further treatment. Furthermore, Ovarian cancer is the most common cause of gynaecological the duration of benefit associated with ‘salvage’ chemotherapy for 8,9 cancer-related deaths and fifth leading cause of death from cancer progression decreases with each subsequent line of treatment. 1,2 in women. Median overall survival (OS) for patients with There remains an unmet need for effective and well-tolerated platinum-sensitive, recurrent ovarian cancer (defined as relapse ≥ long-term maintenance treatment options for patients with 6 months after platinum-based chemotherapy) is 2.5–3 years, and recurrent ovarian cancer to maintain quality of life and delay the patients typically receive a median of four lines of chemotherapy need for further chemotherapy, particularly after response. 3,4 after progression. Progression-free survival (PFS) for these Olaparib (Lynparza™), a poly(adenosine diphosphate–ribose) patients ranges from 8 to 13 months from the start of second- polymerase (PARP) inhibitor, is approved (tablet formulation) for line chemotherapy. In patients who respond to further platinum- treatment in the maintenance setting for patients with platinum- based chemotherapy, the median PFS from the end of treatment sensitive relapsed ovarian cancer, irrespective of BRCA1/2 muta- 5–7 10,11 is consistently 5–6 months and most patients are offered the tion (BRCAm) status. next line of palliative chemotherapy. Cumulative toxicities of We have previously reported data from Study 19 chemotherapy and the emergence of drug resistance limit (NCT00753545), a Phase II trial that assessed the efficacy and 1 2 3 University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, NSW, Australia; Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Research UK 4 5 6 Edinburgh Centre, Western General Hospital, Edinburgh, UK; Kliniken Essen Mitte, Essen, Germany; University of Leuven, Leuven Cancer Institute, Leuven, Belgium; Mount 7 8 9 Vernon Hospital, Northwood, UK; Royal Melbourne Hospital, Parkville, VIC, Australia; University of Düsseldorf, Düsseldorf, Germany; Chaim Sheba Medical Center, Tel 10 11 12 Hashomer, Israel; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Northwestern University Feinberg School 13 14 of Medicine, Chicago, IL, USA; Orenburg Regional Clinical Oncological Dispensary, Orenburg, Russia; Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France; 15 16 17 18 GINECO Group, Paris, France; AstraZeneca, Cambridge, UK; AstraZeneca, Gaithersburg, MD, USA and University College London Cancer Institute, London, UK Correspondence: Michael Friedlander (Michael.friedlander@health.nsw.go.au) Present address: AstraZeneca, Gaithersburg, MD, USA Received: 23 April 2018 Revised: 20 August 2018 Accepted: 4 September 2018 Published online: 24 October 2018 © The Author(s) 2018 Published by Springer Nature on behalf of Cancer Research UK Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. safety of olaparib maintenance monotherapy in platinum-sensi- was a secondary endpoint and we report the final analysis for this tive, recurrent high-grade serous ovarian cancer patients, and outcome here. Patients were monitored for OS with follow-up showed a significant improvement in PFS with maintenance every 12 weeks after treatment discontinuation. Exploratory olaparib vs placebo (hazard ratio (HR) 0.35, 95% confidence analyses of time to first and second subsequent therapy or death interval (CI) 0.25–0.49; P< 0.0001). The PFS prolongation was (TFST, TSST) were also conducted. Safety and tolerability were durable, with 32 of 136 patients (24%) who received olaparib assessed throughout the study by recording adverse events (AEs; being progression-free for >2 years. A pre-planned, retrospective graded using CTCAE v3.0), physical examination results, vital signs analysis of patients in Study 19 demonstrated that BRCAm patients and laboratory findings. derived the greatest clinical benefit from olaparib (HR 0.18, 95% CI 0.10–0.31; P< 0.0001); however, a PFS advantage was also seen for Statistical analyses BRCA wild-type (BRCAwt) patients (HR 0.54, 95% CI 0.34–0.85; P = Study 19 was powered to ensure a sufficient number of PFS events 0.0075). More recently, PFS data from the Phase III SOLO2 trial of in the overall study population; it was not formally powered to olaparib tablets as maintenance monotherapy in patients with assess differences in OS, either between active treatment and platinum-sensitive, relapsed ovarian cancer and a BRCAm con- placebo or within different patient groups. Previous OS analyses firmed a significant benefit for olaparib-treated patients compared are listed in the Supplementary Methods. The final OS analysis for with those who received placebo (HR 0.30, 95% CI 0.22–0.41; P< Study 19, reported here, (79% data maturity; DCO: 9 May 2016; 0.0001). Although the initial analysis of OS in Study 19 (data two-sided α = 0.95%) was protocol defined and the analysis set for maturity: 38%) did not detect a treatment effect, previously OS included all patients randomised to treatment. The results reported updated data from an interim analysis (data cut-off should be regarded as descriptive and P-values as nominal. OS, [DCO] 30 September 2015; data maturity: 77%) suggested an TFST and TSST were analysed using an adjusted Cox proportional advantage in OS for patients receiving olaparib vs placebo (HR hazards model (Supplementary Methods). Restricted means OS 5,14 0.73, 95% CI 0.55–0.96; nominal P = 0.025). analyses were carried out using the pseudovalues method Safety data from clinical trials in recurrent ovarian cancer previously described. patients have shown that olaparib (capsule) monotherapy is generally well tolerated, and data from SOLO2 suggest the new tablet formulation of olaparib has a similar tolerability RESULTS 6,14–18 profile. Furthermore, there was no detriment to health- Study population related quality of life (HRQoL) while on treatment in either Study Of 265 patients randomised in Study 19, 136 were to olaparib and 19,20 19 or SOLO2. Given its clinical profile, long-term administra- 129 to placebo (Fig. 1). BRCAm status was established for 254 of tion of olaparib as maintenance monotherapy in ovarian cancer 265 patients (96%; 131 olaparib vs 123 placebo), including 97 for patients is feasible and an attractive option. Here, we report the whom BRCAm status was known at study entry; 136 patients were final protocol-defined OS analysis from Study 19, characterise classified as BRCAm (74 olaparib vs 62 placebo). At the final DCO (9 those patients who have derived long-term benefit from olaparib May 2016), 14 olaparib-arm patients (10%) and 1 placebo-arm and, in particular, assess the long-term safety and tolerability of patient (1%) were continuing treatment. olaparib treatment. Patient demographics and baseline characteristics were gen- erally well balanced for the overall study population and the 5,13 BRCAm and BRCAwt subgroups. Patients treated with olaparib MATERIALS AND METHODS for over 2 years had similar characteristics to the overall study Study design and population population (Table 1, Supplementary Table 1). Study 19 was a Phase II, randomised, double-blind, placebo- controlled trial (NCT00753545). Eligible patients were at least 18 OS and subsequent anticancer therapy years old, with recurrent ovarian, fallopian tube or primary The final DCO corresponded to 79% OS data maturity (210 deaths peritoneal cancer with high-grade serous histology and were from 265 patients), with a median follow-up of 78.0 months. An platinum sensitive. Patients had received two or more prior apparent advantage in OS for patients randomised to olaparib courses of platinum-based chemotherapy and were in complete maintenance monotherapy vs placebo in the total study popula- or partial response to their most recent regimen (Supplemen- tion (HR 0.73, 95% CI 0.55‒0.95; nominal P = 0.02138; Fig. 2a) did tary Methods). Additional eligibility criteria have been described not meet the threshold defined for statistical significance (P< previously. Known BRCAm status was not required but was 0.0095). A separation in favour of olaparib treatment was seen in established retrospectively by germline or tumour testing for the Kaplan–Meier (KM) curves for the overall study population, patients with appropriate samples available who provided BRCAm and BRCAwt subgroups as duration of follow-up increased consent (Supplementary Methods). (Fig. 2). The separation of the KM curves became more apparent after 36 months of follow-up, reflecting the long-term benefit Treatments derived for olaparib-treated patients. These data are similar to Patients were randomised 1:1 to olaparib or matching placebo, as those reported from the previous DCO (30 September 2015). described previously. Olaparib maintenance monotherapy (400 Although there was little difference in point estimate medians mg bid, capsule formulation) was administered orally and (29.8 months olaparib vs 27.8 placebo), an exploratory restricted treatment continued until disease progression, if toxicities were means OS analysis indicated a difference in survival of 6.1 months manageable (Supplementary Methods). between treatment arms (95% CI −0.3‒12.6; 41.6 months olaparib vs 35.5 placebo). Assessments Although crossover between treatment arms was not permitted Tumour assessments were conducted every 12 weeks until week in Study 19, 17 of 129 patients (13.2%) in the placebo group 60, and every 24 weeks thereafter, until objective disease subsequently received PARP inhibitors via other studies. We progression or withdrawal of consent. Response Evaluation therefore conducted an exploratory post-hoc OS analysis of 103 Criteria in Solid Tumours (RECIST) data were not collected after olaparib-arm and 92 placebo-arm patients by excluding patients the primary DCO (30 June 2010). The primary endpoint of the from sites where at least one patient had received subsequent study was PFS, for which data have been reported previously. OS PARP inhibitor treatment. At the final DCO, this resulted in an 1234567890();,: Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. 326 patients enrolled 61 did not meet eligibility criteria 265 randomised patients 136 assigned to olaparib 129 assigned to placebo 136 received olaparib 128 received placebo 122 discontinued study treatment 8 adverse events 94 condition worsened 127 discontinued study treatment 3 severe protocol non-compliance 2 adverse events 1 lost to follow-up 116 condition worsened 14 voluntary discontinuation 1 severe protocol non-compliance 8 voluntary discontinuation 2 other 14 remained 10 remained 117 discontinued study 108 discontinued study in study in study 98 died 111 died* 3 lost to follow-up 2 lost to follow-up 3 voluntary discontinuation 7 voluntary discontinuation 1 protocol non-compliance 28 still in study at final data cut-off 11 still in study at final data cut-off 14 remaining on randomised treatment 1 remaining on randomised treatment Fig. 1 Patient disposition. *One patient was randomly assigned to the placebo group but withdrew consent and withdrew from the study without receiving treatment. This patient subsequently died but is not included in the number of deaths for patients who discontinued the study after being treated with placebo adjusted OS HR of 0.68 (95% CI 0.49‒0.95; BRCAm see The main reason for discontinuation of study treatment was Supplementary Results). With the exception of PARP inhibitor disease progression (210 of 249 patients; Fig. 1 and Supplemen- treatment, types of subsequent therapy received were similar tary Figure 2). After 2 years on treatment, the rate of discontinua- across both treatment arms (Supplementary Table 2). tion of olaparib decreased. Eighteen patients discontinued after this time; nine due to disease progression, four voluntarily, three Times to first and second subsequent therapy or death due to AEs and two due to protocol non-compliance. Exploratory analyses of TFST (87% data maturity, median follow-up At the final DCO, in the full analysis set, mean (standard 77.4 months) and TSST (85% data maturity, median follow-up deviation) compliance with study treatment (assessed using 77.1 months) were performed at the final DCO (Supplementary capsule counts) was 96.9% (8.9) in the olaparib arm and 99.0% Figure 1). Median TFST and TSST were significantly longer in the (3.4) in the placebo arm. olaparib arm in the overall study population, BRCAm and BRCAwt subgroups. AE profile During Study 19, the most common AEs in the olaparib group Long-term treatment exposure were early onset of nausea (71%), fatigue/asthenia (63%), vomiting At the final DCO (9 May 2016), 15 of 136 patients (11%) (35%) and diarrhoea (27%), consistent with those previously had received maintenance olaparib monotherapy for 6 years or reported. No new safety findings were observed in the overall more; eight of these had a BRCAm and seven were classified as study population and safety findings for BRCAm patients were BRCAwt (Fig. 3), although one BRCAwt patient was subsequently similar to those in the overall population (Supplementary 5,13,14 found to carry a somatic BRCAm following exploratory biomarker Table 3). Exposure-adjusted AE rates are presented in the testing. Supplementary Results. Since the study began, serious AEs (SAEs) Twenty-two of 32 olaparib-arm patients (69%) and all five reported in more than one patient in either treatment group were: placebo-arm patients who were on treatment for at least 2 years anaemia (3 olaparib vs 0 placebo), pancytopenia (2 olaparib were receiving the full treatment dose (400 mg bid) immediately [patients subsequently developed myelodysplastic syndrome prior to discontinuation or the end of follow-up. Eight olaparib- (MDS) and acute myeloid leukaemia (AML), respectively] vs 0 arm patients (25%) were at a reduced dose of 200 mg bid, six of placebo), constipation (2 olaparib vs 0 placebo), gastritis (0 whom had their dose reduced prior to 2 years, with the remaining olaparib vs 2 placebo), small intestinal obstruction (2 olaparib vs 3 two (6%) receiving 100 mg bid, one of whom had their dose placebo), fractured femur (2 olaparib vs 0 placebo) and dyspnoea reduced prior to 2 years. (2 olaparib vs 0 placebo). Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Table 1 Patient demographics and baseline characteristics All patients (n = 265) Patients on treatment ≥ 2 years (n = 37) Olaparib (n = 136) Placebo (n = 129) Olaparib (n = 32) Placebo (n = 5) Age (years) 58.0 (21‒89) 59.0 (33‒84) 60.0 (43‒80) 59.0 (48‒71) Ancestry Non-Jewish 115 (85) 112 (87) 26 (81) 5 (100) Jewish 21 (15) 17 (13) 6 (19) 0 Number of previous lines of chemotherapy 2 59 (43) 63 (49) 14 (44) 3 (60) 3 43 (32) 34 (26) 11 (34) 2 (40) 4 18 (13) 19 (15) 4 (13) 0 ≥5 16 (12) 13 (10) 3 (9) 0 Primary tumour location Ovary 119 (88) 109 (84) 28 (88) 5 (100) Fallopian tube or primary peritoneal 17 (13) 20 (16) 4 (13) 0 Time to progression after completion of penultimate platinum-based regimen >6 to ≤ 12 months 53 (39) 54 (42) 11 (34) 1 (20) >12 months 83 (61) 75 (58) 21 (66) 4 (80) Objective response to most recent platinum-based regimen Complete response 57 (42) 63 (49) 18 (56) 4 (80) Partial response 79 (58) 66 (51) 14 (44) 1 (20) Secondary debulking ≤ 1 month prior to randomisation 22 (16) 13 (10) 8 (25) 0 Metastatic disease at baseline Any site 55 (40) 49 (38) 10 (32) 2 (40) Lymph nodes 26 (19) 10 (8) 4 (13) 1 (20) Peritoneum 20 (15) 11 (9) 2 (6) 1 (20) Hepatic 19 (14) 12 (9) 5 (16) 0 5,14 Data are median (range) or n (%). Some of these baseline data have been previously reported Ancestry was self-reported Including gall bladder Since the last DCO (30 September 2015), three new SAEs were while on study treatment. This was the only case of AML reported in two patients in the olaparib group (non-cardiac chest reported in Study 19; two patients were reported with MDS, as pain and aphasia in one patient, who had previously developed described previously (see Supplementary Results). All three brain lesions, and an incarcerated abdominal hernia in the other patients had previously received two lines of platinum-based patient). chemotherapy. Four olaparib-treated patients developed new A smaller proportion of olaparib-arm patients reported AEs late primary malignancies: adenocarcinoma of the colon, ductal in treatment (75%) compared with the full study duration (97%), carcinoma in situ, papillary thyroid cancer and squamous cell although the prevalence of pruritus, urinary tract infection, carcinoma of the oral cavity (see Supplementary Results). Two dyspnoea and pain in extremity was increased (Table 2a). There cases of pneumonitis were reported during the study, one in the were no AEs for which >20% of patients experienced a new olaparib arm <3 months into treatment, and one in the placebo episode after 2 years of treatment. arm, both of grade 1 severity. Of the 264 patients who received study treatment, 209 deaths Of those patients who received olaparib, throughout the whole had occurred at the time of the final DCO (98 olaparib vs 111 study 53 (39%) had dose interruptions (47 [35%] for AEs) and 59 placebo). In the investigators’ opinion, the vast majority of (43%) had dose reductions (35 [26%] for AEs). In the placebo arm, 23 patients in both treatment groups died because of progression patients (18%) had dose interruptions (13 [10%] for AEs) and 29 of their ovarian cancer (188 patients). Since the study began, patients (23%) had dose reductions (5 [4%] for AEs; BRCAmsee two patients, both in the olaparib arm and both with a BRCAm, Supplementary Results). Since the last DCO, no new AEs have led to experienced AEs that resulted in death. One of these deaths had discontinuation of study treatment. Overall, AEs leading to occurred at the time of the last DCO; this patient died due to discontinuation of study treatment were reported for eight (6%) AEs of haemorrhagic stroke and thrombocytopenia, deemed to olaparib-arm and two (2%) placebo-arm patients (see Supplemen- be treatment related. The other death was due to previously tary Results); no single AE was the reason for discontinuation of more reported AML; this AE occurred 14 days after discontinuation of than one patient in either treatment arm. All AEs leading to study treatment and the patient, who had received olaparib for treatment discontinuation were considered related to study treat- over 4 years, died approximately 1 year and 9 months later. This ment in the investigator’s opinion, and have been previously 5,13,14 patient previously was reported to have a SAE of pancytopenia reported. Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Overall study population Olaparib Placebo 1.0 112/129 (87) Deaths/total patients (%) 98/136 (72) 27.8 (24.9–33.7) 29.8 (26.9–35.7) Median OS, months (95% CI) 0.9 HR 0.73 (95% CI 0.55–0.95); nominal P = 0.02138 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 136 (0) 129 (5) 117 (7) 97 (9) 79 (9) 62 (9) 52 (9) 43 (9) 42 (9) 41 (9) 37 (9) 35 (9) 33 (9) 21 (19) 4 (34) 0 (38) 0 (38) Placebo 129 (0) 122 (3) 112 (4) 90 (4) 75 (5) 57 (5) 44 (5) 37 (5) 32 (5) 27 (5) 24 (6) 18 (6) 14 (6) 9 (9) 1 (16) 0 (17) 0 (17) BRCAm subgroup Olaparib Placebo 1.0 Deaths/total patients (%) 49/74 (66) 50/62 (81) 34.9 (29.2–54.6) 30.2 (23.1–40.7) Median OS, months (95% CI) 0.9 HR 0.62 (95% CI 0.42–0.93); nominal P = 0.02140 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 74 (0) 69 (4) 65 (4) 56 (6) 50 (6) 39 (6) 33 (6) 27 (6) 27 (6) 27 (6) 25 (6) 23 (6) 22 (6) 16 (11) 3 (22) 0 (25) 0 (25) Placebo 62 (0) 58 (2) 52 (3) 40 (3) 34 (4) 29 (4) 25 (4) 20 (4) 19 (4) 15 (4) 13 (5) 10 (5) 9 (5) 6 (6) 0 (12) 0 (12) 0 (12) BRCA wt subgroup Olaparib Placebo 1.0 45/57 (79) 57/61 (93) Deaths/total patients (%) Median OS, months (95% CI) 24.5 (19.8–35.0) 26.6 (23.1–32.5) 0.9 HR 0.84 (95% CI 0.57–1.25); nominal P = 0.39749 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 57 (0) 57 (0) 50 (2) 39 (2) 28 (2) 23 (2) 19 (2) 16 (2) 15 (2) 14 (2) 12 (2) 12 (2) 11 (2) 5 (7) 1 (11) 0 (12) 0 (12) Placebo 61 (0) 60 (0) 56 (0) 46 (0) 37 (0) 25 (0) 17 (0) 15 (0) 12 (0) 12 (0) 11 (0) 8 (0) 5 (0) 3 (2) 1 (3) 0 (4) 0 (4) Fig. 2 Overall survival in all patients and according to BRCA mutation status: a overall study population; b BRCAm subgroup; c BRCAwt subgroup Proportion of patients event-free Proportion of patients event-free Proportion of patients event-free Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Olaparib Placebo Safety analysis set n = 136 n = 128 50 n = 74 BRCAm subgroup n = 62 n = 57 BRCAwt subgroup n = 61 20 11 20 11 8 8 8 18 7 7 14 15 8 3 1 1 1 1 1 0 0 0 0 0 ≥1 ≥2 ≥3 ≥4 ≥5 ≥6 Time on treatment (years) Fig. 3 Duration of exposure to treatment. *Patient numbers are shown on the chart. Ten patients had an unknown BRCAm status Characterisation of common AEs curves between treatment arms seen after approximately 3 5,13 We further characterised the common AEs of nausea, vomiting, years. This is supported by an exploratory restricted means fatigue/asthenia and anaemia in Study 19 by determining their OS analysis, carried out to assess average life-expectancy over the severity and outcome (Table 2b). These events were generally low whole survival curve, taking into account differences in hazard grade, did not require treatment modification, and only two ratio over time. Although consistent with previously reported data patients (one per treatment arm) discontinued treatment due to showing that BRCAm patients had the greatest PFS benefit from common AEs. Anaemia was the most common haematological olaparib, these long-term OS results indicate that a subset of toxicity, occurring in 23 and 7% of olaparib- and placebo-treated patients within the BRCAwt group also experience durable long- patients, respectively. At study entry, 20 patients (15%) in the term benefit from maintenance olaparib monotherapy. It is likely olaparib arm had anaemia vs 14 (11%) in the placebo arm and 18 that these patients have homologous recombination repair (HRR) olaparib-treated patients (13%) received a blood transfusion deficiencies (germline or somatic) resulting in synthetic lethality during the trial, (1 [1%] placebo). Data for BRCAm patients were with exposure to olaparib. Approximately 50% of patients with consistent with those for the overall population (Supplementary high-grade serous ovarian cancer are thought to have a deficiency Tables 5 and 6). in HRR, opening up maintenance therapy for a significant number Patients who experienced common AEs typically did so for the of women with recurrent ovarian cancer. The challenge is to first time within a few months of the start of treatment and it was identify which BRCAwt patients are most likely to benefit from a rare for common AEs to initially develop after >6 months on PARP inhibitor. It has been recently reported that a positive olaparib (event rates < 0.3 per patient year; Fig. 4, Supplementary homologous recombination deficiency (HRD) score was associated Figure 3 [BRCAm patients]). Prevalence plots for the common AEs with long-term response ( > 2 years) to olaparib. Additionally, a show the proportion of patients at risk (receiving treatment or biomarker analysis of patients in Study 19 who remained on within their 30 day follow-up period) who experienced each AE treatment for ≥ 6 years has shown at least 5 of 15 patients were during a specific month. This is irrespective of AE start date, so AEs classified as BRCAwt. This BRCAwt group included patients with with a long duration are represented over multiple months; note other HRR pathway gene mutations or a positive HRD score, as that when there are only a few patients on treatment the well as a patient with no positive candidate predictive biomarker proportion experiencing an AE can appear to be high (Fig. 4, test results. Other baseline characteristics were broadly similar Supplementary Figure 4 [BRCAm patients]). between the full study population and those on long-term treatment, although an increased proportion of patients on olaparib for at least 2 years had undergone secondary debulking DISCUSSION surgery shortly prior to randomisation in Study 19. The long-term We report the final analyses of long-term efficacy and tolerability survivors in this study represent a highly selected subpopulation. data from Study 19, a Phase II trial assessing olaparib maintenance Although it is likely that factors such as patient heterogeneity and monotherapy (400 mg bid, capsule formulation) in patients with the number of subsequent lines of treatment following progres- platinum-sensitive, recurrent high-grade serous ovarian cancer in sion may have contributed to the OS of patients, it should be response to their most recent platinum-based chemotherapy noted that in this randomised trial, 15 (11%) patients were on regimen, representing the longest follow-up from any PARP olaparib for > 6 years, compared with only one (0.8%) placebo inhibitor trial reported. Our findings suggest an OS advantage for recipient. It remains to be established why these patients achieved patients receiving maintenance olaparib vs placebo, an effect not such a durable response to olaparib. yet observed for any chemotherapy regimen or other main- Following progression, OS may be influenced by subsequent 3,24 tenance therapies in the recurrent ovarian cancer setting. It therapy with platinum agents, bevacizumab and/or PARP inhibi- should be noted that although Study 19 was not designed or tors. Crossover was not permitted in our study; however, 13% of powered to show a statistically significant difference in OS, this OS placebo-arm patients subsequently received a PARP inhibitor via advantage with olaparib is consistent with previously published other clinical trials. This could have caused confounding of the OS 5,13,14 analyses. data and, consistent with this, we show an improved OS HR for The apparent OS benefit seen with olaparib appears to be olaparib vs placebo when excluding patients from sites where at driven by long-term responders, with a separation in KM survival least one patient received subsequent treatment with a PARP Patients on treatment (%)* Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Table 2 AEs in Study 19: (a) episodes of any grade occurring after ≥ 2 years on treatment in > 7% of olaparib-arm patients in the overall population or BRCAm subgroup; (b) severity and impact of common AEs on treatment since the start of Study 19 (a) Overall population BRCAm patients Patients on treatment ≥2 years, n (%), preferred term Olaparib, n = 32 Placebo, Olaparib, n = 21 Placebo, n = 5 n = 5 Patients with any AE occurring after 2 years on treatment 24 (75) 4 (80) 16 (76) 4 (80) Fatigue/asthenia 6 (19) 0 4 (19) 0 Constipation 5 (16) 0 4 (19) 0 Pruritus 5 (16) 0 4 (19) 0 Urinary tract infection 5 (16) 0 4 (19) 0 Dizziness 5 (16) 0 3 (14) 0 Dyspnoea 5 (16) 0 3 (14) 0 Nausea 4 (13) 0 3 (14) 0 Abdominal distension 4 (13) 0 3 (14) 0 Back pain 4 (13) 0 3 (14) 0 Upper respiratory tract infection 4 (13) 0 3 (14) 0 Cough 4 (13) 0 2 (10) 0 Pain in extremity 4 (13) 0 2 (10) 0 Anaemia 3 (9) 0 3 (14) 0 Bone pain 3 (9) 0 3 (14) 0 Headache 3 (9) 1 (20) 2 (10) 1 (20) Peripheral swelling 3 (9) 0 2 (10) 0 Blood creatinine increased 3 (9) 0 1 (5) 0 Diarrhoea 3 (9) 0 1 (5) 0 Sinusitis 3 (9) 0 1 (5) 0 Vomiting 3 (9) 0 1 (5) 0 Abdominal pain 2 (6) 1 (20) 2 (10) 1 (20) Alopecia 2 (6) 0 2 (10) 0 Cystitis 2 (6) 0 2 (10) 0 Ecchymosis 2 (6) 0 2 (10) 0 Osteoarthritis 2 (6) 0 2 (10) 0 Pancytopenia 2 (6) 0 2 (10) 0 Pyrexia 2 (6) 0 2 (10) 0 Sensory disturbance 2 (6) 0 2 (10) 0 Sleep disorder 2 (6) 0 2 (10) 0 (b) Nausea Vomiting Fatigue/asthenia Anaemia Olaparib Placebo Olaparib Placebo Olaparib Placebo Olaparib Placebo n 136 128 136 128 136 128 136 128 Patients with AEs 96 (71) 46 (36) 48 (35) 18 (14) 86 (63) 59 (46) 31 (23) 9 (7) Patients whose first incidence occurred after >6 months on 12 (9) 4 (3) 11 (8) 4 (3) 18 (13) 4 (3) 10 (7) 0 treatment Total episodes 129 58 92 20 118 72 40 10 Grade 1 102 (79) 46 (79) 66 (72) 12 (60) 69 (58) 58 (81) 5 (13) 6 (60) Grade 2 24 (19) 12 (21) 23 (25) 7 (35) 37 (31) 10 (14) 24 (60) 3 (30) Grade 3 or 4 3 (2) 0 3 (3) 1 (5) 12 (10) 4 (6) 11 (28) 1 (10) Treatment interrupted 9 (7) 1 (2) 18 (20) 1 (5) 8 (7) 2 (3) 4 (10) 0 Treatment dose reduced 5 (4) 0 4 (4) 1 (5) 9 (8) 1 (1) 8 (20) 1 (10) Treatment discontinued 1 (1) 1 (2) 0 0 0 0 0 0 AE resolved 105 (81) 46 (79) 90 (98) 17 (85) 73 (62) 35 (49) 28 (70) 7 (70) Treatment required 56 (43) 10 (17) 21 (23) 3 (15) 5 (4) 3 (4) 30 (75) 2 (20) Median time to onset of first event, days 4.0 13.0 52.0 64.5 28.0 29.0 29.0 92.0 Median duration of first event, months 2.7 0.8 0.1 0.1 3.0 3.3 2.8 0.5 Arbitrary cut-off corresponding to three or more patients in the overall population, or two or more patients in the BRCAm subgroup All AEs reported after 2 years of treatment are included irrespective of whether this was the first incidence of a specific AE; incidences that began before 2 years, but that continued past 2 years on treatment are not included; no AEs were reported after 2 years by more than one patient in the placebo arm AE adverse event Includes patients with anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased Patients could experience more than one episode of the AE Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. inhibitor, confirming similar findings from an earlier interim of time that patients spent on olaparib compared with placebo, it analysis. This approach, excluding sites, was preferred to a is expected that more AEs will be observed in the olaparib arm. similar method excluding just crossover patients as it was felt to Exposure-adjusted AE data (Supplementary Table 4), which show lessen the potential confounding of removing only well- the number of AEs per year on treatment, demonstrate more performing placebo patients and better retain the benefits of limited differences between the two treatment groups for the randomisation. As PARP inhibitors become more commonly common AEs and show a higher rate of fatigue/asthenia in the utilised and widely available, the feasibility of showing a placebo arm; this suggests that the prevalence of this AE is similar statistically significant OS benefit is decreasing; no future trials irrespective of treatment arm, and that fatigue/asthenia may not will be able to have as little crossover as Study 19 and, given the be caused by olaparib. results of this and other maintenance studies with PARP inhibitors, These safety data should be considered in the context of placebo-controlled trials would no longer be ethical in this toxicity profiles associated with palliative chemotherapy, which is population. commonly prescribed to patients at disease progression. There are Exploratory data for TFST and TSST reported here show many potential adverse effects (AEs) associated with chemother- significant benefits with maintenance olaparib monotherapy apy, which can be cumulative, limiting the length of time patients compared with placebo for the overall population and for the can remain on treatment. Currently, the reporting of AEs with BRCAm and BRCAwt subgroups, consistent with previous ana- PARP inhibitors is based on an approach developed for AEs 13,14 lyses. A clear separation between the olaparib and placebo KM associated with chemotherapy and arguably, new methods of AE survival curves can be seen extending past 6 years of follow-up. reporting, including patient reported AEs, may be more appro- Since no tumour assessments were carried out in Study 19 after priate for characterising the intermittent AEs typically observed the primary DCO (30 June 2010), TFST represents a reasonable with PARP inhibitors. In this study, intermittent AEs could have long-term surrogate for PFS, which was analysed with a median of been reported differently by individual investigators, either as a 5.6 months’ follow-up. TFST and TSST data are consistent with the single event of long duration or multiple events of short duration. observed advantage in PFS and OS for olaparib-arm patients and This inconsistency may have resulted in higher prevalence being show a clinically meaningful increase in time between chemother- observed for events such as nausea, and fatigue/asthenia that had apy regimens, while also suggesting an extended efficacy benefit a long median duration (and may have been intermittent during with olaparib persisting beyond the next line of therapy. this time). The generally low-grade, non-cumulative nature of the The long-term exposure seen in Study 19 is unprecedented for common AEs observed with olaparib in Study 19 supports the a PARP inhibitor; consistently across BRCAm and BRCAwt approach that they can be routinely managed by physicians subgroups, 10% of patients experienced a durable benefit from through dose modifications when required and symptomatic olaparib maintenance monotherapy for over 6 years. Almost 25% treatment with standard procedures, such as antiemetics or of patients received olaparib for at least 2 years (compared with occasional blood transfusions, although regular haematological 10,11,28 4% of placebo-arm patients), considerably longer than the monitoring is recommended for patients receiving olaparib. 5–7 expected median PFS of 4–6 months in this population. A Various factors should be considered when weighing the value higher proportion of patients who received olaparib long term of long-term maintenance therapy with a PARP inhibitor against had at least three prior lines of chemotherapy compared with platinum-based chemotherapy alone followed by further lines of those who received placebo. The rate of discontinuation of treatment for recurrent disease at symptomatic progression. olaparib for any reason decreased after 2 years, suggesting Maintenance olaparib may not be effective in all patients, and is patients who reach this milestone are likely to receive continued often associated with low-grade intermittent toxicity that can benefit from maintenance olaparib. It should be noted that usually be controlled with simple supportive measures. However, patients continued treatment long-term despite taking 16 large its efficacy and generally favourable long-term tolerability profile, capsules per day; a more patient-friendly formulation of olaparib, coupled with previously reported data showing no detrimental 10,11 19 requiring only 4 tablets per day, is now available. impact on patients’ HRQoL during treatment, makes olaparib a No new safety signals were identified since the previous viable maintenance treatment option following response to analysis and data reported here indicate that the tolerability platinum-based chemotherapy, which should be discussed with profile of olaparib is compatible with long-term treatment. Very patients. Maintenance therapy with olaparib capsules prolonged few patients discontinued treatment due to AEs in Study 19; 6 and PFS in Study 19, and results from the ongoing Phase III SOLO2 2% in the olaparib and placebo arms, respectively. The majority of trial of maintenance therapy with the tablet formulation of patients receiving olaparib long term were on full dose olaparib also showed a significant increase in median PFS for immediately prior to the end of treatment, which suggests BRCAm patients, compared with placebo. Long-term follow-up enduring dose modifications are not required to maintain long- from SOLO2 and other ongoing trials will help further elucidate term tolerability. the efficacy and tolerability profiles of olaparib maintenance AEs of MDS and AML were rare in Study 19 and were reported monotherapy and ultimately identify those patients with ovarian in both treatment arms. The incidence in Study 19 was broadly cancer most likely to receive long-term benefit from maintenance consistent with that seen in SOLO2. The MDS, AML and new therapy with olaparib. primary malignancy AEs that occurred in Study 19 were unrelated In addition, patient preference data showing the trade-off that to duration of exposure to olaparib. women with recurrent ovarian cancer who are receiving main- 16–18 In line with previously published olaparib data, the most tenance PARP inhibitor therapy are willing to make in terms of common AEs in Study 19 were low-grade nausea, fatigue/asthenia gains in PFS and OS vs avoiding toxicity are also needed. Survey and vomiting, with anaemia the most common haematological results indicate that most women with recurrent ovarian cancer AE. These AEs usually occurred early and rarely first developed required an increase in PFS of at least 5 months to make treatment after >6 months on olaparib or placebo. Only one patient worthwhile, and patient preference data suggest that women discontinued olaparib due to one of these common AEs (nausea). with recurrent ovarian cancer would accept a shorter PFS in order Prevalence data show that the proportion of patients who to avoid severe adverse effects associated with chemotherapy experienced vomiting or anaemia during any specific month (e.g., nausea, vomiting). A delay in the time to subsequent was low. More patients at a given time experienced nausea and chemotherapy is also likely to be of importance to patients, with fatigue/asthenia, however, there was no increase in prevalence of TFST and TSST significantly prolonged with olaparib vs placebo in these AEs with long-term treatment. Due to the increased length both Study 19 and SOLO2. Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. a b Time to first event of vomiting Time to first event of nausea 14 2.0 1.8 Olaparib Olaparib 1.6 Placebo Placebo 1.4 1.2 7 1.0 0.8 0.6 0.4 0.2 0 0.0 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 Months from first dose Months from first dose Events (patients at risk) 80 (136) 35 (128) 8 (56) 5 (93) 5 (43) 3 (82) 3 (31) 3 (40) 0 (16) 0 (13) 0 (8) 0 (3) 0 (7) 0 (2) 0 (6) 0 (1) Events (patients at risk) 20 (136) 5 (128) 9 (116) 8 (123) 13 (101) 3 (106) 4 (72) 2 (54) 1 (37) 0 (15) 0 (21) 0 (5) 1 (15) 0 (3) 0 (12) 0 (1) Exposure in interval, years 5.9 8.8 8.3 14.7 9.2 14.8 11.0 10.5 10.7 6.6 7.2 2.3 6.3 1.8 14.9 3.0 Exposure in interval, years 10.2 10.4 18.1 19.4 20.9 19.2 25.1 12.9 27.2 8.6 18.6 3.7 12.8 2.7 28.2 3.0 c d Time to first event of anaemia Time to first event of fatigue/asthenia 6 1.5 1.4 1.3 5 Olaparib Olaparib 1.2 Placebo Placebo 1.1 4 1.0 0.9 0.8 0.7 0.6 2 0.5 0.4 0.3 0.2 0.1 0.0 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 Months from first dose Months from first dose Events (patients at risk) 48 (136) 36 (128) 26 (88) 17 (92) 3 (54) 4 (67) 3 (43) 0 (35) 4 (21) 2 (11) 1 (13) 0 (3) 1 (7) 0 (2) 0 (5) 0 (1) Events (patients at risk) 16 (136) 1 (128) 8 (120) 3 (127) 2 (103) 5 (115) 3 (80) 0 (52) 0 (45) 0 (15) 0 (26) 0 (5) 1 (20) 0 (3) 1 (17) 0 (1) Exposure in interval, years 8.8 9.2 11.6 13.3 11.8 12.6 14.6 9.6 15.8 5.3 9.5 2.3 5.5 2.0 11.8 3.0 Exposure in interval, years 10.7 10.6 18.3 20.6 22.5 20.1 29.0 13.2 31.9 8.6 22.9 3.7 17.9 2.7 34.7 3.0 e f Prevalence of vomiting Prevalence of nausea 1.0 1.0 AE toxicity grade 0.9 AE toxicity grade 0.9 1 1 0.8 0.8 2 2 0.7 0.7 3 3 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 Months from first dose Months from first dose n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 g h Prevalence of fatigue/asthenia Prevalence of anaemia 1.0 1.0 AE toxicity grade AE toxicity grade 0.9 0.9 1 1 0.8 0.8 2 2 0.7 0.7 3 3 4 4 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 1 3 6 9 121518213 2427 0334 3639 2455 4851 4576 6063 6697 7275 8 Months from first dose Months from first dose n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 Fig. 4 Characterisation of common AEs: time to first event (Event rate = number of first events/exposure during time interval. Note that y axes scales are different between parts a, b, c and d)of a nausea, b vomiting, c fatigue/asthenia and d anaemia , and prevalence by month and † † grade of e nausea, f vomiting, g fatigue/asthenia and h anaemia in olaparib-treated patients. Includes patients with anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased CONCLUSIONS despite considerable crossover. This finding is supported by The final analysis from Study 19 is the largest long-term survival significant improvements in PFS, TFST and TSST with maintenance follow-up data for a PARP inhibitor and suggests an OS advantage olaparib compared with placebo in BRCAmor BRCAwt women. with olaparib maintenance monotherapy for patients with Almost 25% of patients in Study 19 received olaparib for at least 2 platinum-sensitive, recurrent high-grade serous ovarian cancer. years and over 10% continued on treatment for 6 years or more, Although the threshold for statistical significance was not met, a demonstrating a prolonged, clinically meaningful benefit derived numerical OS advantage was seen, irrespective of BRCAm status, from olaparib maintenance therapy, which is unprecedented in Proportion of patients experiencing event Proportion of patients experiencing event Event rate per patient years Event rate per patient years Event rate per patient years Proportion of patients experiencing event Proportion of patients experiencing event Event rate per patient years Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. patients with recurrent ovarian cancer. The capsule formulation of 2. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014). olaparib was well tolerated in Study 19; the majority of AEs in both 3. Aghajanian, C. et al. Final overall survival and safety analysis of OCEANS, a phase the overall population and BRCAm subgroup were low grade and 3 trial of chemotherapy with or without bevacizumab in patients with platinum- manageable with dose modifications or simple supportive sensitive recurrent ovarian cancer. Gynecol. Oncol. 139,10–16 (2015). treatments and no new tolerability signals were identified with 4. Wagner, U. et al. Final overall survival results of phase III GCIG CALYPSO trial of long-term treatment. Taken together, these data support the use pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in of olaparib maintenance monotherapy as long-term treatment for platinum-sensitive ovarian cancer patients. Br. J. Cancer 107, 588–591 patients with platinum-sensitive, recurrent high-grade serous (2012). ovarian cancer with or without a BRCAm. 5. Ledermann, J. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366, 1382–1392 (2012). 6. Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ ACKNOWLEDGEMENTS ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Medical writing support during the development of this manuscript was provided by Lancet Oncol. 18, 1274–1284 (2017). Elin Pyke, MChem from Mudskipper Business Ltd and was funded by AstraZeneca. M. 7. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent F. is supported by an NHMRC Program Grant, ID: APP1092856. ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016). 8. Ledermann, J. A. et al. Newly diagnosed and relapsed epithelial ovarian carci- noma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. AUTHOR CONTRIBUTIONS Ann. Oncol. 24, vi24–vi32 (2013). J.L. was responsible for the study design. M.F., U.M., C.G., A.dB., I.V., G.R., C.S., W.M., R. 9. Hanker, L. C. et al. The impact of second to sixth line therapy on survival of S.-F., T.S., D.M., V.S., F.S. and J.L. obtained the data. A.F., E.S.L., E.L.M., S.S., P.R., H.M. and relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann. D.P. analysed the data. All authors interpreted the data and reviewed the draft and Oncol. 23, 2605–2612 (2012). final versions of the manuscript. 10. FDA. Lynparza prescribing information (2017 update). 2014. Available at: https:// www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. 11. European Medicines Agency. Lynparza summary of product characteristics. 2018. DATA AVAILABILITY Available at: http://ec.europa.eu/health/documents/community-register/2018/ AstraZeneca’s policy on clinical trial data, results and other information from or 20180508140545/anx_140545_en.pdf. regarding AstraZeneca-sponsored clinical trials are described in full the AstraZeneca 12. Lheureux, S. et al. Long-term responders on olaparib maintenance in high-grade website: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Search. serous ovarian cancer: clinical and molecular characterization. Clin. Cancer Res. 23, 4086–4094 (2017). 13. Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum- sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of ADDITIONAL INFORMATION outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, Supplementary information is available for this paper at https://doi.org/10.1038/ 852–861 (2014). s41416-018-0271-y. 14. Ledermann, J. A. et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: Competing interests: M.F. has received personal fees from Astra Zeneca and MSD. C. an updated analysis from a randomised, placebo-controlled, double-blind, phase G. has received grants and personal fees from AstraZeneca, Tesaro and Nucana, 2 trial. Lancet Oncol. 17, 1579–1589 (2016). grants from Novartis and Aprea, personal fees from Clovis, Roche and Foundation 15. Ledermann, J. A. et al. Adverse events (AEs) with maintenance olaparib tablets in One, and has a patent issued (PCT/US2012/040805) and patents pending (PCT/ patients (pts) with BRCA-mutated (BRCAm) platinum-sensitive relapsed serous GB2013/053202, 1409479.1, 1409476.7 and 1409478.3). A.dB. has received personal ovarian cancer (PSR SOC): Phase III SOLO2 trial. J. Clin. Oncol. 35, 5518 (2017). fees from Roche, AstraZeneca, Tesaro, Pharmamar and Pfizer. I.V. has received Abstr. personal fees from GCI Health, Oncoinvent AS, Roche NV, Genmab A/S, Advaxis Inc., 16. Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in Morphotek Inc., F Hoffmann-La Roche Ltd, Cerulean Pharma Inc., Novocure GMBH, patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof- AstraZeneca LP, Mateon Therapeutics Inc., Immunogen Inc., Eli Lilly Benelux NV, of-concept trial. Lancet 376, 245–251 (2010). Amgen Inc., Theradex Europe Limited, Pfizer Inc., Debiopharma International SA, Vifor 17. Gelmon, K. A. et al. Olaparib in patients with recurrent high-grade serous or Pharma België NV, Novartis Pharma AG, MSD Belgium BVBA, Oxigene Inc., Janssen- poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase Cilag, Nektar Therapeutics and Bayer Pharma AG, grants from Amgen and Roche, and 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 support for accommodation and travel from Tesaro, Theradex and Elsevier. G.R. has (2011). received personal fees from AstraZeneca and Roche. C.S. has received non-financial 18. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a support and other from AstraZeneca, non-financial support from Clovis Oncology and germ-line BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015). Eisai Oncology, and grants and non-financial support from Roche. R.S.-F. has received 19. Ledermann, J. A. et al. Quality of life during olaparib maintenance therapy in honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis and Roche. D.M. has platinum-sensitive relapsed serous ovarian cancer. Br. J. Cancer 115, 1313–1320 received personal fees from Clovis, Astex Inc., Roche and Tesaro. F.S. has received (2016). personal fees from Roche, AstraZeneca, Tesaro and Pharmamar. J.L. has received 20. Friedlander, M. et al. Health-related quality of life (HRQOL) and patient-centered institutional and personal fees from AstraZeneca; personal fees from Roche, Pfizer, outcomes with maintenance olaparib compared with placebo following che- Clovis Oncology and Seattle Genetics; and institutional fees from Merck/MSD. A.F., E. motherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive L., E.M., S.S., H.M. and D.P. are employees of AstraZeneca and own stock. P.R. is an relapsed serous ovarian cancer (PSR SOC): SOLO2 phase III trial. J. Clin. Oncol. 35, employee of AstraZeneca. 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Cancer 122, 1844–1852 adaptation, distribution and reproduction in any medium or format, as long as you give (2016). appropriate credit to the original author(s) and the source, provide a link to the Creative 27. Matulonis, U. A., Oza, A. M., Ho, T. W. & Ledermann, J. A. Intermediate clinical Commons license, and indicate if changes were made. The images or other third party endpoints: a bridge between progression-free survival and overall survival in material in this article are included in the article’s Creative Commons license, unless ovarian cancer trials. Cancer 121, 1737–1746 (2015). indicated otherwise in a credit line to the material. If material is not included in the 28. Friedlander, M. et al. 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Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

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Springer Journals
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Copyright © 2018 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
DOI
10.1038/s41416-018-0271-y
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Abstract

www.nature.com/bjc ARTICLE Clinical Study Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy 1 2 3 4 5 6 7 Michael Friedlander , Ursula Matulonis , Charlie Gourley , Andreas du Bois , Ignace Vergote , Gordon Rustin , Clare Scott , 8 9 10,11 12 13 14,15 16,19 Werner Meier , Ronnie Shapira-Frommer , Tamar Safra , Daniela Matei , Vadim Shirinkin , Frédéric Selle , Anitra Fielding , 17 16 16 16 16 16 18 Elizabeth S. Lowe , Emma L. McMurtry , Stuart Spencer , Philip Rowe , Helen Mann , David Parry and Jonathan Ledermann BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long- term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients. British Journal of Cancer (2018) 119:1075–1085; https://doi.org/10.1038/s41416-018-0271-y INTRODUCTION delivery and potential benefit of further treatment. Furthermore, Ovarian cancer is the most common cause of gynaecological the duration of benefit associated with ‘salvage’ chemotherapy for 8,9 cancer-related deaths and fifth leading cause of death from cancer progression decreases with each subsequent line of treatment. 1,2 in women. Median overall survival (OS) for patients with There remains an unmet need for effective and well-tolerated platinum-sensitive, recurrent ovarian cancer (defined as relapse ≥ long-term maintenance treatment options for patients with 6 months after platinum-based chemotherapy) is 2.5–3 years, and recurrent ovarian cancer to maintain quality of life and delay the patients typically receive a median of four lines of chemotherapy need for further chemotherapy, particularly after response. 3,4 after progression. Progression-free survival (PFS) for these Olaparib (Lynparza™), a poly(adenosine diphosphate–ribose) patients ranges from 8 to 13 months from the start of second- polymerase (PARP) inhibitor, is approved (tablet formulation) for line chemotherapy. In patients who respond to further platinum- treatment in the maintenance setting for patients with platinum- based chemotherapy, the median PFS from the end of treatment sensitive relapsed ovarian cancer, irrespective of BRCA1/2 muta- 5–7 10,11 is consistently 5–6 months and most patients are offered the tion (BRCAm) status. next line of palliative chemotherapy. Cumulative toxicities of We have previously reported data from Study 19 chemotherapy and the emergence of drug resistance limit (NCT00753545), a Phase II trial that assessed the efficacy and 1 2 3 University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, NSW, Australia; Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Research UK 4 5 6 Edinburgh Centre, Western General Hospital, Edinburgh, UK; Kliniken Essen Mitte, Essen, Germany; University of Leuven, Leuven Cancer Institute, Leuven, Belgium; Mount 7 8 9 Vernon Hospital, Northwood, UK; Royal Melbourne Hospital, Parkville, VIC, Australia; University of Düsseldorf, Düsseldorf, Germany; Chaim Sheba Medical Center, Tel 10 11 12 Hashomer, Israel; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Northwestern University Feinberg School 13 14 of Medicine, Chicago, IL, USA; Orenburg Regional Clinical Oncological Dispensary, Orenburg, Russia; Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France; 15 16 17 18 GINECO Group, Paris, France; AstraZeneca, Cambridge, UK; AstraZeneca, Gaithersburg, MD, USA and University College London Cancer Institute, London, UK Correspondence: Michael Friedlander (Michael.friedlander@health.nsw.go.au) Present address: AstraZeneca, Gaithersburg, MD, USA Received: 23 April 2018 Revised: 20 August 2018 Accepted: 4 September 2018 Published online: 24 October 2018 © The Author(s) 2018 Published by Springer Nature on behalf of Cancer Research UK Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. safety of olaparib maintenance monotherapy in platinum-sensi- was a secondary endpoint and we report the final analysis for this tive, recurrent high-grade serous ovarian cancer patients, and outcome here. Patients were monitored for OS with follow-up showed a significant improvement in PFS with maintenance every 12 weeks after treatment discontinuation. Exploratory olaparib vs placebo (hazard ratio (HR) 0.35, 95% confidence analyses of time to first and second subsequent therapy or death interval (CI) 0.25–0.49; P< 0.0001). The PFS prolongation was (TFST, TSST) were also conducted. Safety and tolerability were durable, with 32 of 136 patients (24%) who received olaparib assessed throughout the study by recording adverse events (AEs; being progression-free for >2 years. A pre-planned, retrospective graded using CTCAE v3.0), physical examination results, vital signs analysis of patients in Study 19 demonstrated that BRCAm patients and laboratory findings. derived the greatest clinical benefit from olaparib (HR 0.18, 95% CI 0.10–0.31; P< 0.0001); however, a PFS advantage was also seen for Statistical analyses BRCA wild-type (BRCAwt) patients (HR 0.54, 95% CI 0.34–0.85; P = Study 19 was powered to ensure a sufficient number of PFS events 0.0075). More recently, PFS data from the Phase III SOLO2 trial of in the overall study population; it was not formally powered to olaparib tablets as maintenance monotherapy in patients with assess differences in OS, either between active treatment and platinum-sensitive, relapsed ovarian cancer and a BRCAm con- placebo or within different patient groups. Previous OS analyses firmed a significant benefit for olaparib-treated patients compared are listed in the Supplementary Methods. The final OS analysis for with those who received placebo (HR 0.30, 95% CI 0.22–0.41; P< Study 19, reported here, (79% data maturity; DCO: 9 May 2016; 0.0001). Although the initial analysis of OS in Study 19 (data two-sided α = 0.95%) was protocol defined and the analysis set for maturity: 38%) did not detect a treatment effect, previously OS included all patients randomised to treatment. The results reported updated data from an interim analysis (data cut-off should be regarded as descriptive and P-values as nominal. OS, [DCO] 30 September 2015; data maturity: 77%) suggested an TFST and TSST were analysed using an adjusted Cox proportional advantage in OS for patients receiving olaparib vs placebo (HR hazards model (Supplementary Methods). Restricted means OS 5,14 0.73, 95% CI 0.55–0.96; nominal P = 0.025). analyses were carried out using the pseudovalues method Safety data from clinical trials in recurrent ovarian cancer previously described. patients have shown that olaparib (capsule) monotherapy is generally well tolerated, and data from SOLO2 suggest the new tablet formulation of olaparib has a similar tolerability RESULTS 6,14–18 profile. Furthermore, there was no detriment to health- Study population related quality of life (HRQoL) while on treatment in either Study Of 265 patients randomised in Study 19, 136 were to olaparib and 19,20 19 or SOLO2. Given its clinical profile, long-term administra- 129 to placebo (Fig. 1). BRCAm status was established for 254 of tion of olaparib as maintenance monotherapy in ovarian cancer 265 patients (96%; 131 olaparib vs 123 placebo), including 97 for patients is feasible and an attractive option. Here, we report the whom BRCAm status was known at study entry; 136 patients were final protocol-defined OS analysis from Study 19, characterise classified as BRCAm (74 olaparib vs 62 placebo). At the final DCO (9 those patients who have derived long-term benefit from olaparib May 2016), 14 olaparib-arm patients (10%) and 1 placebo-arm and, in particular, assess the long-term safety and tolerability of patient (1%) were continuing treatment. olaparib treatment. Patient demographics and baseline characteristics were gen- erally well balanced for the overall study population and the 5,13 BRCAm and BRCAwt subgroups. Patients treated with olaparib MATERIALS AND METHODS for over 2 years had similar characteristics to the overall study Study design and population population (Table 1, Supplementary Table 1). Study 19 was a Phase II, randomised, double-blind, placebo- controlled trial (NCT00753545). Eligible patients were at least 18 OS and subsequent anticancer therapy years old, with recurrent ovarian, fallopian tube or primary The final DCO corresponded to 79% OS data maturity (210 deaths peritoneal cancer with high-grade serous histology and were from 265 patients), with a median follow-up of 78.0 months. An platinum sensitive. Patients had received two or more prior apparent advantage in OS for patients randomised to olaparib courses of platinum-based chemotherapy and were in complete maintenance monotherapy vs placebo in the total study popula- or partial response to their most recent regimen (Supplemen- tion (HR 0.73, 95% CI 0.55‒0.95; nominal P = 0.02138; Fig. 2a) did tary Methods). Additional eligibility criteria have been described not meet the threshold defined for statistical significance (P< previously. Known BRCAm status was not required but was 0.0095). A separation in favour of olaparib treatment was seen in established retrospectively by germline or tumour testing for the Kaplan–Meier (KM) curves for the overall study population, patients with appropriate samples available who provided BRCAm and BRCAwt subgroups as duration of follow-up increased consent (Supplementary Methods). (Fig. 2). The separation of the KM curves became more apparent after 36 months of follow-up, reflecting the long-term benefit Treatments derived for olaparib-treated patients. These data are similar to Patients were randomised 1:1 to olaparib or matching placebo, as those reported from the previous DCO (30 September 2015). described previously. Olaparib maintenance monotherapy (400 Although there was little difference in point estimate medians mg bid, capsule formulation) was administered orally and (29.8 months olaparib vs 27.8 placebo), an exploratory restricted treatment continued until disease progression, if toxicities were means OS analysis indicated a difference in survival of 6.1 months manageable (Supplementary Methods). between treatment arms (95% CI −0.3‒12.6; 41.6 months olaparib vs 35.5 placebo). Assessments Although crossover between treatment arms was not permitted Tumour assessments were conducted every 12 weeks until week in Study 19, 17 of 129 patients (13.2%) in the placebo group 60, and every 24 weeks thereafter, until objective disease subsequently received PARP inhibitors via other studies. We progression or withdrawal of consent. Response Evaluation therefore conducted an exploratory post-hoc OS analysis of 103 Criteria in Solid Tumours (RECIST) data were not collected after olaparib-arm and 92 placebo-arm patients by excluding patients the primary DCO (30 June 2010). The primary endpoint of the from sites where at least one patient had received subsequent study was PFS, for which data have been reported previously. OS PARP inhibitor treatment. At the final DCO, this resulted in an 1234567890();,: Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. 326 patients enrolled 61 did not meet eligibility criteria 265 randomised patients 136 assigned to olaparib 129 assigned to placebo 136 received olaparib 128 received placebo 122 discontinued study treatment 8 adverse events 94 condition worsened 127 discontinued study treatment 3 severe protocol non-compliance 2 adverse events 1 lost to follow-up 116 condition worsened 14 voluntary discontinuation 1 severe protocol non-compliance 8 voluntary discontinuation 2 other 14 remained 10 remained 117 discontinued study 108 discontinued study in study in study 98 died 111 died* 3 lost to follow-up 2 lost to follow-up 3 voluntary discontinuation 7 voluntary discontinuation 1 protocol non-compliance 28 still in study at final data cut-off 11 still in study at final data cut-off 14 remaining on randomised treatment 1 remaining on randomised treatment Fig. 1 Patient disposition. *One patient was randomly assigned to the placebo group but withdrew consent and withdrew from the study without receiving treatment. This patient subsequently died but is not included in the number of deaths for patients who discontinued the study after being treated with placebo adjusted OS HR of 0.68 (95% CI 0.49‒0.95; BRCAm see The main reason for discontinuation of study treatment was Supplementary Results). With the exception of PARP inhibitor disease progression (210 of 249 patients; Fig. 1 and Supplemen- treatment, types of subsequent therapy received were similar tary Figure 2). After 2 years on treatment, the rate of discontinua- across both treatment arms (Supplementary Table 2). tion of olaparib decreased. Eighteen patients discontinued after this time; nine due to disease progression, four voluntarily, three Times to first and second subsequent therapy or death due to AEs and two due to protocol non-compliance. Exploratory analyses of TFST (87% data maturity, median follow-up At the final DCO, in the full analysis set, mean (standard 77.4 months) and TSST (85% data maturity, median follow-up deviation) compliance with study treatment (assessed using 77.1 months) were performed at the final DCO (Supplementary capsule counts) was 96.9% (8.9) in the olaparib arm and 99.0% Figure 1). Median TFST and TSST were significantly longer in the (3.4) in the placebo arm. olaparib arm in the overall study population, BRCAm and BRCAwt subgroups. AE profile During Study 19, the most common AEs in the olaparib group Long-term treatment exposure were early onset of nausea (71%), fatigue/asthenia (63%), vomiting At the final DCO (9 May 2016), 15 of 136 patients (11%) (35%) and diarrhoea (27%), consistent with those previously had received maintenance olaparib monotherapy for 6 years or reported. No new safety findings were observed in the overall more; eight of these had a BRCAm and seven were classified as study population and safety findings for BRCAm patients were BRCAwt (Fig. 3), although one BRCAwt patient was subsequently similar to those in the overall population (Supplementary 5,13,14 found to carry a somatic BRCAm following exploratory biomarker Table 3). Exposure-adjusted AE rates are presented in the testing. Supplementary Results. Since the study began, serious AEs (SAEs) Twenty-two of 32 olaparib-arm patients (69%) and all five reported in more than one patient in either treatment group were: placebo-arm patients who were on treatment for at least 2 years anaemia (3 olaparib vs 0 placebo), pancytopenia (2 olaparib were receiving the full treatment dose (400 mg bid) immediately [patients subsequently developed myelodysplastic syndrome prior to discontinuation or the end of follow-up. Eight olaparib- (MDS) and acute myeloid leukaemia (AML), respectively] vs 0 arm patients (25%) were at a reduced dose of 200 mg bid, six of placebo), constipation (2 olaparib vs 0 placebo), gastritis (0 whom had their dose reduced prior to 2 years, with the remaining olaparib vs 2 placebo), small intestinal obstruction (2 olaparib vs 3 two (6%) receiving 100 mg bid, one of whom had their dose placebo), fractured femur (2 olaparib vs 0 placebo) and dyspnoea reduced prior to 2 years. (2 olaparib vs 0 placebo). Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Table 1 Patient demographics and baseline characteristics All patients (n = 265) Patients on treatment ≥ 2 years (n = 37) Olaparib (n = 136) Placebo (n = 129) Olaparib (n = 32) Placebo (n = 5) Age (years) 58.0 (21‒89) 59.0 (33‒84) 60.0 (43‒80) 59.0 (48‒71) Ancestry Non-Jewish 115 (85) 112 (87) 26 (81) 5 (100) Jewish 21 (15) 17 (13) 6 (19) 0 Number of previous lines of chemotherapy 2 59 (43) 63 (49) 14 (44) 3 (60) 3 43 (32) 34 (26) 11 (34) 2 (40) 4 18 (13) 19 (15) 4 (13) 0 ≥5 16 (12) 13 (10) 3 (9) 0 Primary tumour location Ovary 119 (88) 109 (84) 28 (88) 5 (100) Fallopian tube or primary peritoneal 17 (13) 20 (16) 4 (13) 0 Time to progression after completion of penultimate platinum-based regimen >6 to ≤ 12 months 53 (39) 54 (42) 11 (34) 1 (20) >12 months 83 (61) 75 (58) 21 (66) 4 (80) Objective response to most recent platinum-based regimen Complete response 57 (42) 63 (49) 18 (56) 4 (80) Partial response 79 (58) 66 (51) 14 (44) 1 (20) Secondary debulking ≤ 1 month prior to randomisation 22 (16) 13 (10) 8 (25) 0 Metastatic disease at baseline Any site 55 (40) 49 (38) 10 (32) 2 (40) Lymph nodes 26 (19) 10 (8) 4 (13) 1 (20) Peritoneum 20 (15) 11 (9) 2 (6) 1 (20) Hepatic 19 (14) 12 (9) 5 (16) 0 5,14 Data are median (range) or n (%). Some of these baseline data have been previously reported Ancestry was self-reported Including gall bladder Since the last DCO (30 September 2015), three new SAEs were while on study treatment. This was the only case of AML reported in two patients in the olaparib group (non-cardiac chest reported in Study 19; two patients were reported with MDS, as pain and aphasia in one patient, who had previously developed described previously (see Supplementary Results). All three brain lesions, and an incarcerated abdominal hernia in the other patients had previously received two lines of platinum-based patient). chemotherapy. Four olaparib-treated patients developed new A smaller proportion of olaparib-arm patients reported AEs late primary malignancies: adenocarcinoma of the colon, ductal in treatment (75%) compared with the full study duration (97%), carcinoma in situ, papillary thyroid cancer and squamous cell although the prevalence of pruritus, urinary tract infection, carcinoma of the oral cavity (see Supplementary Results). Two dyspnoea and pain in extremity was increased (Table 2a). There cases of pneumonitis were reported during the study, one in the were no AEs for which >20% of patients experienced a new olaparib arm <3 months into treatment, and one in the placebo episode after 2 years of treatment. arm, both of grade 1 severity. Of the 264 patients who received study treatment, 209 deaths Of those patients who received olaparib, throughout the whole had occurred at the time of the final DCO (98 olaparib vs 111 study 53 (39%) had dose interruptions (47 [35%] for AEs) and 59 placebo). In the investigators’ opinion, the vast majority of (43%) had dose reductions (35 [26%] for AEs). In the placebo arm, 23 patients in both treatment groups died because of progression patients (18%) had dose interruptions (13 [10%] for AEs) and 29 of their ovarian cancer (188 patients). Since the study began, patients (23%) had dose reductions (5 [4%] for AEs; BRCAmsee two patients, both in the olaparib arm and both with a BRCAm, Supplementary Results). Since the last DCO, no new AEs have led to experienced AEs that resulted in death. One of these deaths had discontinuation of study treatment. Overall, AEs leading to occurred at the time of the last DCO; this patient died due to discontinuation of study treatment were reported for eight (6%) AEs of haemorrhagic stroke and thrombocytopenia, deemed to olaparib-arm and two (2%) placebo-arm patients (see Supplemen- be treatment related. The other death was due to previously tary Results); no single AE was the reason for discontinuation of more reported AML; this AE occurred 14 days after discontinuation of than one patient in either treatment arm. All AEs leading to study treatment and the patient, who had received olaparib for treatment discontinuation were considered related to study treat- over 4 years, died approximately 1 year and 9 months later. This ment in the investigator’s opinion, and have been previously 5,13,14 patient previously was reported to have a SAE of pancytopenia reported. Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Overall study population Olaparib Placebo 1.0 112/129 (87) Deaths/total patients (%) 98/136 (72) 27.8 (24.9–33.7) 29.8 (26.9–35.7) Median OS, months (95% CI) 0.9 HR 0.73 (95% CI 0.55–0.95); nominal P = 0.02138 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 136 (0) 129 (5) 117 (7) 97 (9) 79 (9) 62 (9) 52 (9) 43 (9) 42 (9) 41 (9) 37 (9) 35 (9) 33 (9) 21 (19) 4 (34) 0 (38) 0 (38) Placebo 129 (0) 122 (3) 112 (4) 90 (4) 75 (5) 57 (5) 44 (5) 37 (5) 32 (5) 27 (5) 24 (6) 18 (6) 14 (6) 9 (9) 1 (16) 0 (17) 0 (17) BRCAm subgroup Olaparib Placebo 1.0 Deaths/total patients (%) 49/74 (66) 50/62 (81) 34.9 (29.2–54.6) 30.2 (23.1–40.7) Median OS, months (95% CI) 0.9 HR 0.62 (95% CI 0.42–0.93); nominal P = 0.02140 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 74 (0) 69 (4) 65 (4) 56 (6) 50 (6) 39 (6) 33 (6) 27 (6) 27 (6) 27 (6) 25 (6) 23 (6) 22 (6) 16 (11) 3 (22) 0 (25) 0 (25) Placebo 62 (0) 58 (2) 52 (3) 40 (3) 34 (4) 29 (4) 25 (4) 20 (4) 19 (4) 15 (4) 13 (5) 10 (5) 9 (5) 6 (6) 0 (12) 0 (12) 0 (12) BRCA wt subgroup Olaparib Placebo 1.0 45/57 (79) 57/61 (93) Deaths/total patients (%) Median OS, months (95% CI) 24.5 (19.8–35.0) 26.6 (23.1–32.5) 0.9 HR 0.84 (95% CI 0.57–1.25); nominal P = 0.39749 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Olaparib 0.1 Placebo 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time from randomisation (months) Number of patients at risk (number censored) Olaparib 400 mg bid 57 (0) 57 (0) 50 (2) 39 (2) 28 (2) 23 (2) 19 (2) 16 (2) 15 (2) 14 (2) 12 (2) 12 (2) 11 (2) 5 (7) 1 (11) 0 (12) 0 (12) Placebo 61 (0) 60 (0) 56 (0) 46 (0) 37 (0) 25 (0) 17 (0) 15 (0) 12 (0) 12 (0) 11 (0) 8 (0) 5 (0) 3 (2) 1 (3) 0 (4) 0 (4) Fig. 2 Overall survival in all patients and according to BRCA mutation status: a overall study population; b BRCAm subgroup; c BRCAwt subgroup Proportion of patients event-free Proportion of patients event-free Proportion of patients event-free Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Olaparib Placebo Safety analysis set n = 136 n = 128 50 n = 74 BRCAm subgroup n = 62 n = 57 BRCAwt subgroup n = 61 20 11 20 11 8 8 8 18 7 7 14 15 8 3 1 1 1 1 1 0 0 0 0 0 ≥1 ≥2 ≥3 ≥4 ≥5 ≥6 Time on treatment (years) Fig. 3 Duration of exposure to treatment. *Patient numbers are shown on the chart. Ten patients had an unknown BRCAm status Characterisation of common AEs curves between treatment arms seen after approximately 3 5,13 We further characterised the common AEs of nausea, vomiting, years. This is supported by an exploratory restricted means fatigue/asthenia and anaemia in Study 19 by determining their OS analysis, carried out to assess average life-expectancy over the severity and outcome (Table 2b). These events were generally low whole survival curve, taking into account differences in hazard grade, did not require treatment modification, and only two ratio over time. Although consistent with previously reported data patients (one per treatment arm) discontinued treatment due to showing that BRCAm patients had the greatest PFS benefit from common AEs. Anaemia was the most common haematological olaparib, these long-term OS results indicate that a subset of toxicity, occurring in 23 and 7% of olaparib- and placebo-treated patients within the BRCAwt group also experience durable long- patients, respectively. At study entry, 20 patients (15%) in the term benefit from maintenance olaparib monotherapy. It is likely olaparib arm had anaemia vs 14 (11%) in the placebo arm and 18 that these patients have homologous recombination repair (HRR) olaparib-treated patients (13%) received a blood transfusion deficiencies (germline or somatic) resulting in synthetic lethality during the trial, (1 [1%] placebo). Data for BRCAm patients were with exposure to olaparib. Approximately 50% of patients with consistent with those for the overall population (Supplementary high-grade serous ovarian cancer are thought to have a deficiency Tables 5 and 6). in HRR, opening up maintenance therapy for a significant number Patients who experienced common AEs typically did so for the of women with recurrent ovarian cancer. The challenge is to first time within a few months of the start of treatment and it was identify which BRCAwt patients are most likely to benefit from a rare for common AEs to initially develop after >6 months on PARP inhibitor. It has been recently reported that a positive olaparib (event rates < 0.3 per patient year; Fig. 4, Supplementary homologous recombination deficiency (HRD) score was associated Figure 3 [BRCAm patients]). Prevalence plots for the common AEs with long-term response ( > 2 years) to olaparib. Additionally, a show the proportion of patients at risk (receiving treatment or biomarker analysis of patients in Study 19 who remained on within their 30 day follow-up period) who experienced each AE treatment for ≥ 6 years has shown at least 5 of 15 patients were during a specific month. This is irrespective of AE start date, so AEs classified as BRCAwt. This BRCAwt group included patients with with a long duration are represented over multiple months; note other HRR pathway gene mutations or a positive HRD score, as that when there are only a few patients on treatment the well as a patient with no positive candidate predictive biomarker proportion experiencing an AE can appear to be high (Fig. 4, test results. Other baseline characteristics were broadly similar Supplementary Figure 4 [BRCAm patients]). between the full study population and those on long-term treatment, although an increased proportion of patients on olaparib for at least 2 years had undergone secondary debulking DISCUSSION surgery shortly prior to randomisation in Study 19. The long-term We report the final analyses of long-term efficacy and tolerability survivors in this study represent a highly selected subpopulation. data from Study 19, a Phase II trial assessing olaparib maintenance Although it is likely that factors such as patient heterogeneity and monotherapy (400 mg bid, capsule formulation) in patients with the number of subsequent lines of treatment following progres- platinum-sensitive, recurrent high-grade serous ovarian cancer in sion may have contributed to the OS of patients, it should be response to their most recent platinum-based chemotherapy noted that in this randomised trial, 15 (11%) patients were on regimen, representing the longest follow-up from any PARP olaparib for > 6 years, compared with only one (0.8%) placebo inhibitor trial reported. Our findings suggest an OS advantage for recipient. It remains to be established why these patients achieved patients receiving maintenance olaparib vs placebo, an effect not such a durable response to olaparib. yet observed for any chemotherapy regimen or other main- Following progression, OS may be influenced by subsequent 3,24 tenance therapies in the recurrent ovarian cancer setting. It therapy with platinum agents, bevacizumab and/or PARP inhibi- should be noted that although Study 19 was not designed or tors. Crossover was not permitted in our study; however, 13% of powered to show a statistically significant difference in OS, this OS placebo-arm patients subsequently received a PARP inhibitor via advantage with olaparib is consistent with previously published other clinical trials. This could have caused confounding of the OS 5,13,14 analyses. data and, consistent with this, we show an improved OS HR for The apparent OS benefit seen with olaparib appears to be olaparib vs placebo when excluding patients from sites where at driven by long-term responders, with a separation in KM survival least one patient received subsequent treatment with a PARP Patients on treatment (%)* Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. Table 2 AEs in Study 19: (a) episodes of any grade occurring after ≥ 2 years on treatment in > 7% of olaparib-arm patients in the overall population or BRCAm subgroup; (b) severity and impact of common AEs on treatment since the start of Study 19 (a) Overall population BRCAm patients Patients on treatment ≥2 years, n (%), preferred term Olaparib, n = 32 Placebo, Olaparib, n = 21 Placebo, n = 5 n = 5 Patients with any AE occurring after 2 years on treatment 24 (75) 4 (80) 16 (76) 4 (80) Fatigue/asthenia 6 (19) 0 4 (19) 0 Constipation 5 (16) 0 4 (19) 0 Pruritus 5 (16) 0 4 (19) 0 Urinary tract infection 5 (16) 0 4 (19) 0 Dizziness 5 (16) 0 3 (14) 0 Dyspnoea 5 (16) 0 3 (14) 0 Nausea 4 (13) 0 3 (14) 0 Abdominal distension 4 (13) 0 3 (14) 0 Back pain 4 (13) 0 3 (14) 0 Upper respiratory tract infection 4 (13) 0 3 (14) 0 Cough 4 (13) 0 2 (10) 0 Pain in extremity 4 (13) 0 2 (10) 0 Anaemia 3 (9) 0 3 (14) 0 Bone pain 3 (9) 0 3 (14) 0 Headache 3 (9) 1 (20) 2 (10) 1 (20) Peripheral swelling 3 (9) 0 2 (10) 0 Blood creatinine increased 3 (9) 0 1 (5) 0 Diarrhoea 3 (9) 0 1 (5) 0 Sinusitis 3 (9) 0 1 (5) 0 Vomiting 3 (9) 0 1 (5) 0 Abdominal pain 2 (6) 1 (20) 2 (10) 1 (20) Alopecia 2 (6) 0 2 (10) 0 Cystitis 2 (6) 0 2 (10) 0 Ecchymosis 2 (6) 0 2 (10) 0 Osteoarthritis 2 (6) 0 2 (10) 0 Pancytopenia 2 (6) 0 2 (10) 0 Pyrexia 2 (6) 0 2 (10) 0 Sensory disturbance 2 (6) 0 2 (10) 0 Sleep disorder 2 (6) 0 2 (10) 0 (b) Nausea Vomiting Fatigue/asthenia Anaemia Olaparib Placebo Olaparib Placebo Olaparib Placebo Olaparib Placebo n 136 128 136 128 136 128 136 128 Patients with AEs 96 (71) 46 (36) 48 (35) 18 (14) 86 (63) 59 (46) 31 (23) 9 (7) Patients whose first incidence occurred after >6 months on 12 (9) 4 (3) 11 (8) 4 (3) 18 (13) 4 (3) 10 (7) 0 treatment Total episodes 129 58 92 20 118 72 40 10 Grade 1 102 (79) 46 (79) 66 (72) 12 (60) 69 (58) 58 (81) 5 (13) 6 (60) Grade 2 24 (19) 12 (21) 23 (25) 7 (35) 37 (31) 10 (14) 24 (60) 3 (30) Grade 3 or 4 3 (2) 0 3 (3) 1 (5) 12 (10) 4 (6) 11 (28) 1 (10) Treatment interrupted 9 (7) 1 (2) 18 (20) 1 (5) 8 (7) 2 (3) 4 (10) 0 Treatment dose reduced 5 (4) 0 4 (4) 1 (5) 9 (8) 1 (1) 8 (20) 1 (10) Treatment discontinued 1 (1) 1 (2) 0 0 0 0 0 0 AE resolved 105 (81) 46 (79) 90 (98) 17 (85) 73 (62) 35 (49) 28 (70) 7 (70) Treatment required 56 (43) 10 (17) 21 (23) 3 (15) 5 (4) 3 (4) 30 (75) 2 (20) Median time to onset of first event, days 4.0 13.0 52.0 64.5 28.0 29.0 29.0 92.0 Median duration of first event, months 2.7 0.8 0.1 0.1 3.0 3.3 2.8 0.5 Arbitrary cut-off corresponding to three or more patients in the overall population, or two or more patients in the BRCAm subgroup All AEs reported after 2 years of treatment are included irrespective of whether this was the first incidence of a specific AE; incidences that began before 2 years, but that continued past 2 years on treatment are not included; no AEs were reported after 2 years by more than one patient in the placebo arm AE adverse event Includes patients with anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased Patients could experience more than one episode of the AE Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. inhibitor, confirming similar findings from an earlier interim of time that patients spent on olaparib compared with placebo, it analysis. This approach, excluding sites, was preferred to a is expected that more AEs will be observed in the olaparib arm. similar method excluding just crossover patients as it was felt to Exposure-adjusted AE data (Supplementary Table 4), which show lessen the potential confounding of removing only well- the number of AEs per year on treatment, demonstrate more performing placebo patients and better retain the benefits of limited differences between the two treatment groups for the randomisation. As PARP inhibitors become more commonly common AEs and show a higher rate of fatigue/asthenia in the utilised and widely available, the feasibility of showing a placebo arm; this suggests that the prevalence of this AE is similar statistically significant OS benefit is decreasing; no future trials irrespective of treatment arm, and that fatigue/asthenia may not will be able to have as little crossover as Study 19 and, given the be caused by olaparib. results of this and other maintenance studies with PARP inhibitors, These safety data should be considered in the context of placebo-controlled trials would no longer be ethical in this toxicity profiles associated with palliative chemotherapy, which is population. commonly prescribed to patients at disease progression. There are Exploratory data for TFST and TSST reported here show many potential adverse effects (AEs) associated with chemother- significant benefits with maintenance olaparib monotherapy apy, which can be cumulative, limiting the length of time patients compared with placebo for the overall population and for the can remain on treatment. Currently, the reporting of AEs with BRCAm and BRCAwt subgroups, consistent with previous ana- PARP inhibitors is based on an approach developed for AEs 13,14 lyses. A clear separation between the olaparib and placebo KM associated with chemotherapy and arguably, new methods of AE survival curves can be seen extending past 6 years of follow-up. reporting, including patient reported AEs, may be more appro- Since no tumour assessments were carried out in Study 19 after priate for characterising the intermittent AEs typically observed the primary DCO (30 June 2010), TFST represents a reasonable with PARP inhibitors. In this study, intermittent AEs could have long-term surrogate for PFS, which was analysed with a median of been reported differently by individual investigators, either as a 5.6 months’ follow-up. TFST and TSST data are consistent with the single event of long duration or multiple events of short duration. observed advantage in PFS and OS for olaparib-arm patients and This inconsistency may have resulted in higher prevalence being show a clinically meaningful increase in time between chemother- observed for events such as nausea, and fatigue/asthenia that had apy regimens, while also suggesting an extended efficacy benefit a long median duration (and may have been intermittent during with olaparib persisting beyond the next line of therapy. this time). The generally low-grade, non-cumulative nature of the The long-term exposure seen in Study 19 is unprecedented for common AEs observed with olaparib in Study 19 supports the a PARP inhibitor; consistently across BRCAm and BRCAwt approach that they can be routinely managed by physicians subgroups, 10% of patients experienced a durable benefit from through dose modifications when required and symptomatic olaparib maintenance monotherapy for over 6 years. Almost 25% treatment with standard procedures, such as antiemetics or of patients received olaparib for at least 2 years (compared with occasional blood transfusions, although regular haematological 10,11,28 4% of placebo-arm patients), considerably longer than the monitoring is recommended for patients receiving olaparib. 5–7 expected median PFS of 4–6 months in this population. A Various factors should be considered when weighing the value higher proportion of patients who received olaparib long term of long-term maintenance therapy with a PARP inhibitor against had at least three prior lines of chemotherapy compared with platinum-based chemotherapy alone followed by further lines of those who received placebo. The rate of discontinuation of treatment for recurrent disease at symptomatic progression. olaparib for any reason decreased after 2 years, suggesting Maintenance olaparib may not be effective in all patients, and is patients who reach this milestone are likely to receive continued often associated with low-grade intermittent toxicity that can benefit from maintenance olaparib. It should be noted that usually be controlled with simple supportive measures. However, patients continued treatment long-term despite taking 16 large its efficacy and generally favourable long-term tolerability profile, capsules per day; a more patient-friendly formulation of olaparib, coupled with previously reported data showing no detrimental 10,11 19 requiring only 4 tablets per day, is now available. impact on patients’ HRQoL during treatment, makes olaparib a No new safety signals were identified since the previous viable maintenance treatment option following response to analysis and data reported here indicate that the tolerability platinum-based chemotherapy, which should be discussed with profile of olaparib is compatible with long-term treatment. Very patients. Maintenance therapy with olaparib capsules prolonged few patients discontinued treatment due to AEs in Study 19; 6 and PFS in Study 19, and results from the ongoing Phase III SOLO2 2% in the olaparib and placebo arms, respectively. The majority of trial of maintenance therapy with the tablet formulation of patients receiving olaparib long term were on full dose olaparib also showed a significant increase in median PFS for immediately prior to the end of treatment, which suggests BRCAm patients, compared with placebo. Long-term follow-up enduring dose modifications are not required to maintain long- from SOLO2 and other ongoing trials will help further elucidate term tolerability. the efficacy and tolerability profiles of olaparib maintenance AEs of MDS and AML were rare in Study 19 and were reported monotherapy and ultimately identify those patients with ovarian in both treatment arms. The incidence in Study 19 was broadly cancer most likely to receive long-term benefit from maintenance consistent with that seen in SOLO2. The MDS, AML and new therapy with olaparib. primary malignancy AEs that occurred in Study 19 were unrelated In addition, patient preference data showing the trade-off that to duration of exposure to olaparib. women with recurrent ovarian cancer who are receiving main- 16–18 In line with previously published olaparib data, the most tenance PARP inhibitor therapy are willing to make in terms of common AEs in Study 19 were low-grade nausea, fatigue/asthenia gains in PFS and OS vs avoiding toxicity are also needed. Survey and vomiting, with anaemia the most common haematological results indicate that most women with recurrent ovarian cancer AE. These AEs usually occurred early and rarely first developed required an increase in PFS of at least 5 months to make treatment after >6 months on olaparib or placebo. Only one patient worthwhile, and patient preference data suggest that women discontinued olaparib due to one of these common AEs (nausea). with recurrent ovarian cancer would accept a shorter PFS in order Prevalence data show that the proportion of patients who to avoid severe adverse effects associated with chemotherapy experienced vomiting or anaemia during any specific month (e.g., nausea, vomiting). A delay in the time to subsequent was low. More patients at a given time experienced nausea and chemotherapy is also likely to be of importance to patients, with fatigue/asthenia, however, there was no increase in prevalence of TFST and TSST significantly prolonged with olaparib vs placebo in these AEs with long-term treatment. Due to the increased length both Study 19 and SOLO2. Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. a b Time to first event of vomiting Time to first event of nausea 14 2.0 1.8 Olaparib Olaparib 1.6 Placebo Placebo 1.4 1.2 7 1.0 0.8 0.6 0.4 0.2 0 0.0 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 Months from first dose Months from first dose Events (patients at risk) 80 (136) 35 (128) 8 (56) 5 (93) 5 (43) 3 (82) 3 (31) 3 (40) 0 (16) 0 (13) 0 (8) 0 (3) 0 (7) 0 (2) 0 (6) 0 (1) Events (patients at risk) 20 (136) 5 (128) 9 (116) 8 (123) 13 (101) 3 (106) 4 (72) 2 (54) 1 (37) 0 (15) 0 (21) 0 (5) 1 (15) 0 (3) 0 (12) 0 (1) Exposure in interval, years 5.9 8.8 8.3 14.7 9.2 14.8 11.0 10.5 10.7 6.6 7.2 2.3 6.3 1.8 14.9 3.0 Exposure in interval, years 10.2 10.4 18.1 19.4 20.9 19.2 25.1 12.9 27.2 8.6 18.6 3.7 12.8 2.7 28.2 3.0 c d Time to first event of anaemia Time to first event of fatigue/asthenia 6 1.5 1.4 1.3 5 Olaparib Olaparib 1.2 Placebo Placebo 1.1 4 1.0 0.9 0.8 0.7 0.6 2 0.5 0.4 0.3 0.2 0.1 0.0 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 0–1 >1–3 >3–6 >6–12 >12–24 >24–36 >36–48 >48 Months from first dose Months from first dose Events (patients at risk) 48 (136) 36 (128) 26 (88) 17 (92) 3 (54) 4 (67) 3 (43) 0 (35) 4 (21) 2 (11) 1 (13) 0 (3) 1 (7) 0 (2) 0 (5) 0 (1) Events (patients at risk) 16 (136) 1 (128) 8 (120) 3 (127) 2 (103) 5 (115) 3 (80) 0 (52) 0 (45) 0 (15) 0 (26) 0 (5) 1 (20) 0 (3) 1 (17) 0 (1) Exposure in interval, years 8.8 9.2 11.6 13.3 11.8 12.6 14.6 9.6 15.8 5.3 9.5 2.3 5.5 2.0 11.8 3.0 Exposure in interval, years 10.7 10.6 18.3 20.6 22.5 20.1 29.0 13.2 31.9 8.6 22.9 3.7 17.9 2.7 34.7 3.0 e f Prevalence of vomiting Prevalence of nausea 1.0 1.0 AE toxicity grade 0.9 AE toxicity grade 0.9 1 1 0.8 0.8 2 2 0.7 0.7 3 3 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 Months from first dose Months from first dose n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 g h Prevalence of fatigue/asthenia Prevalence of anaemia 1.0 1.0 AE toxicity grade AE toxicity grade 0.9 0.9 1 1 0.8 0.8 2 2 0.7 0.7 3 3 4 4 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 1 3 6 9 1215 1821 2427 3033 3639 4245 4851 5457 6063 6669 7275 78 1 3 6 9 121518213 2427 0334 3639 2455 4851 4576 6063 6697 7275 8 Months from first dose Months from first dose n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 n at risk 136 132 106 79 65 46 40 38 35 30 29 28 25 24 22 21 21 20 19 19 18 18 17 17 15 15 11 Fig. 4 Characterisation of common AEs: time to first event (Event rate = number of first events/exposure during time interval. Note that y axes scales are different between parts a, b, c and d)of a nausea, b vomiting, c fatigue/asthenia and d anaemia , and prevalence by month and † † grade of e nausea, f vomiting, g fatigue/asthenia and h anaemia in olaparib-treated patients. Includes patients with anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased CONCLUSIONS despite considerable crossover. This finding is supported by The final analysis from Study 19 is the largest long-term survival significant improvements in PFS, TFST and TSST with maintenance follow-up data for a PARP inhibitor and suggests an OS advantage olaparib compared with placebo in BRCAmor BRCAwt women. with olaparib maintenance monotherapy for patients with Almost 25% of patients in Study 19 received olaparib for at least 2 platinum-sensitive, recurrent high-grade serous ovarian cancer. years and over 10% continued on treatment for 6 years or more, Although the threshold for statistical significance was not met, a demonstrating a prolonged, clinically meaningful benefit derived numerical OS advantage was seen, irrespective of BRCAm status, from olaparib maintenance therapy, which is unprecedented in Proportion of patients experiencing event Proportion of patients experiencing event Event rate per patient years Event rate per patient years Event rate per patient years Proportion of patients experiencing event Proportion of patients experiencing event Event rate per patient years Long-term efficacy, tolerability and overall survival in patients with. . . M Friedlander et al. patients with recurrent ovarian cancer. The capsule formulation of 2. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014). olaparib was well tolerated in Study 19; the majority of AEs in both 3. Aghajanian, C. et al. Final overall survival and safety analysis of OCEANS, a phase the overall population and BRCAm subgroup were low grade and 3 trial of chemotherapy with or without bevacizumab in patients with platinum- manageable with dose modifications or simple supportive sensitive recurrent ovarian cancer. Gynecol. Oncol. 139,10–16 (2015). treatments and no new tolerability signals were identified with 4. Wagner, U. et al. Final overall survival results of phase III GCIG CALYPSO trial of long-term treatment. Taken together, these data support the use pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in of olaparib maintenance monotherapy as long-term treatment for platinum-sensitive ovarian cancer patients. Br. J. Cancer 107, 588–591 patients with platinum-sensitive, recurrent high-grade serous (2012). ovarian cancer with or without a BRCAm. 5. Ledermann, J. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366, 1382–1392 (2012). 6. Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ ACKNOWLEDGEMENTS ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Medical writing support during the development of this manuscript was provided by Lancet Oncol. 18, 1274–1284 (2017). Elin Pyke, MChem from Mudskipper Business Ltd and was funded by AstraZeneca. M. 7. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent F. is supported by an NHMRC Program Grant, ID: APP1092856. ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016). 8. Ledermann, J. A. et al. Newly diagnosed and relapsed epithelial ovarian carci- noma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. AUTHOR CONTRIBUTIONS Ann. Oncol. 24, vi24–vi32 (2013). J.L. was responsible for the study design. M.F., U.M., C.G., A.dB., I.V., G.R., C.S., W.M., R. 9. Hanker, L. C. et al. The impact of second to sixth line therapy on survival of S.-F., T.S., D.M., V.S., F.S. and J.L. obtained the data. A.F., E.S.L., E.L.M., S.S., P.R., H.M. and relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann. D.P. analysed the data. All authors interpreted the data and reviewed the draft and Oncol. 23, 2605–2612 (2012). final versions of the manuscript. 10. FDA. Lynparza prescribing information (2017 update). 2014. Available at: https:// www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. 11. European Medicines Agency. Lynparza summary of product characteristics. 2018. DATA AVAILABILITY Available at: http://ec.europa.eu/health/documents/community-register/2018/ AstraZeneca’s policy on clinical trial data, results and other information from or 20180508140545/anx_140545_en.pdf. regarding AstraZeneca-sponsored clinical trials are described in full the AstraZeneca 12. Lheureux, S. et al. Long-term responders on olaparib maintenance in high-grade website: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Search. serous ovarian cancer: clinical and molecular characterization. Clin. Cancer Res. 23, 4086–4094 (2017). 13. Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum- sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of ADDITIONAL INFORMATION outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, Supplementary information is available for this paper at https://doi.org/10.1038/ 852–861 (2014). s41416-018-0271-y. 14. Ledermann, J. A. et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: Competing interests: M.F. has received personal fees from Astra Zeneca and MSD. C. an updated analysis from a randomised, placebo-controlled, double-blind, phase G. has received grants and personal fees from AstraZeneca, Tesaro and Nucana, 2 trial. Lancet Oncol. 17, 1579–1589 (2016). grants from Novartis and Aprea, personal fees from Clovis, Roche and Foundation 15. Ledermann, J. A. et al. Adverse events (AEs) with maintenance olaparib tablets in One, and has a patent issued (PCT/US2012/040805) and patents pending (PCT/ patients (pts) with BRCA-mutated (BRCAm) platinum-sensitive relapsed serous GB2013/053202, 1409479.1, 1409476.7 and 1409478.3). A.dB. has received personal ovarian cancer (PSR SOC): Phase III SOLO2 trial. J. Clin. Oncol. 35, 5518 (2017). fees from Roche, AstraZeneca, Tesaro, Pharmamar and Pfizer. I.V. has received Abstr. personal fees from GCI Health, Oncoinvent AS, Roche NV, Genmab A/S, Advaxis Inc., 16. Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in Morphotek Inc., F Hoffmann-La Roche Ltd, Cerulean Pharma Inc., Novocure GMBH, patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof- AstraZeneca LP, Mateon Therapeutics Inc., Immunogen Inc., Eli Lilly Benelux NV, of-concept trial. Lancet 376, 245–251 (2010). Amgen Inc., Theradex Europe Limited, Pfizer Inc., Debiopharma International SA, Vifor 17. Gelmon, K. A. et al. Olaparib in patients with recurrent high-grade serous or Pharma België NV, Novartis Pharma AG, MSD Belgium BVBA, Oxigene Inc., Janssen- poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase Cilag, Nektar Therapeutics and Bayer Pharma AG, grants from Amgen and Roche, and 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 support for accommodation and travel from Tesaro, Theradex and Elsevier. G.R. has (2011). received personal fees from AstraZeneca and Roche. C.S. has received non-financial 18. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a support and other from AstraZeneca, non-financial support from Clovis Oncology and germ-line BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015). Eisai Oncology, and grants and non-financial support from Roche. R.S.-F. has received 19. Ledermann, J. A. et al. Quality of life during olaparib maintenance therapy in honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis and Roche. D.M. has platinum-sensitive relapsed serous ovarian cancer. Br. J. Cancer 115, 1313–1320 received personal fees from Clovis, Astex Inc., Roche and Tesaro. F.S. has received (2016). personal fees from Roche, AstraZeneca, Tesaro and Pharmamar. J.L. has received 20. Friedlander, M. et al. Health-related quality of life (HRQOL) and patient-centered institutional and personal fees from AstraZeneca; personal fees from Roche, Pfizer, outcomes with maintenance olaparib compared with placebo following che- Clovis Oncology and Seattle Genetics; and institutional fees from Merck/MSD. A.F., E. motherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive L., E.M., S.S., H.M. and D.P. are employees of AstraZeneca and own stock. P.R. is an relapsed serous ovarian cancer (PSR SOC): SOLO2 phase III trial. J. Clin. Oncol. 35, employee of AstraZeneca. 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Published: Oct 24, 2018

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