Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial

Summary

Background

In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm).

Methods

In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years’ follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided α of 0·95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545.

Findings

Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0·73 [95% CI 0·55–0·96]; nominal p=0·025, which did not meet the required threshold for statistical significance [p<0·0095]; median overall survival was 29·8 months [95% CI 26·9–35·7] for those treated with olaparib vs 27·8 months [24·9–33·7] for those treated with placebo), and in patients with BRCAm (HR 0·62 [95% CI 0·41–0·94] nominal p=0·025; 34·9 months [95% CI 29·2–54·6] vs 30·2 months [23·1–40·7]). The overall survival data in patients with BRCA wild-type were HR 0·83 (95% CI 0·55–1·24, nominal p=0·37; 24·5 months [19·8–35·0] for those treated with olaparib vs 26·6 months [23·1–32·5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment.

Interpretation

Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer.

Funding

AstraZeneca.

Introduction

Ovarian cancer is the fifth most common type of cancer for women in developed countries.1, 2 About 70% of patients relapse within 3 years of completing first-line chemotherapy and the mean 5 year survival rate in Europe is low when compared with other tumour types (about 38%).3, 4, 5 Overall, ovarian cancer is the sixth highest cause of cancer-related deaths for women in high-income countries.1, 2

Olaparib (Lynparza) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor that has shown significant clinical activity in ovarian cancer, particularly in tumours that have mutations in BRCA1 and BRCA2 (BRCAm).6, 7, 8 Olaparib traps PARP at sites of DNA damage, blocking base-excision repair and resulting in the collapse of DNA replication forks and the accumulation of DNA double-strand breaks.⁹ Induced synthetic lethality is seen with olaparib in tumours that are deficient in homologous recombination repair pathways, such as those with BRCAm.10, 11

Previously, we reported data from a randomised, double-blind, phase 2 trial (NCT00753545, D0810C00019 [Study 19]) that showed a significant improvement in progression-free survival for patients with platinum-sensitive, recurrent, serous ovarian cancer who received olaparib maintenance monotherapy, compared with placebo (hazard ratio [HR] 0·35 [95% CI 0·25–0·49]; p<0·0001).6, 7 A pre-planned analysis of the retrospectively identified BRCA-mutated subgroup showed that patients with BRCAm derived the greatest progression-free survival benefit from olaparib (HR 0·18 [0·10–0·31]; p<0·0001).⁷ A significant improvement in time to first subsequent therapy or death and time to second subsequent therapy or death was also reported with maintenance olaparib compared with placebo.⁷ On the basis of these data, olaparib (as capsules; 400 mg twice a day) was approved in the European Union as maintenance treatment for patients with platinum-sensitive, relapsed, BRCA-mutated ovarian cancer.¹² Olaparib is also approved in the USA as monotherapy for patients with germline BRCA-mutated advanced ovarian cancer.¹³ This indication was based on data from another phase 2 study (NCT01078662, D0810C00042 [Study 42]).⁸

Two interim analyses of overall survival from Study 19 have previously been done, at 38% data maturity (HR 0·94 [95% CI 0·63–1·39]; p=0·75) and 58% data maturity (0·88 [0·64–1·21]; p=0·44) in the overall study population.6, 7 In this Article, we present an updated descriptive overall survival analysis following the deaths of 203 (77%) of 265 patients in this study, with an additional 3 years of overall survival follow-up since the previous analysis. We assessed the effect of maintenance olaparib on overall survival in women with platinum-sensitive recurrent serous ovarian cancer.