Elsevier

The Lancet Oncology

Volume 22, Issue 5, May 2021, Pages 620-631
The Lancet Oncology

Articles
Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(21)00073-5Get rights and content

Summary

Background

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival.

Methods

This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0–1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients.

Findings

Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6–69·3) with olaparib and 64·5 months (63·4–68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5–59·1) with olaparib and 38·8 months (31·4–48·6) with placebo (hazard ratio 0·74 [95% CI 0·54–1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]).

Interpretation

Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.

Funding

AstraZeneca and Merck.

Introduction

Patients with relapsed ovarian cancer usually receive multiple lines of chemotherapy, with time to relapse typically shortening with each successive line of treatment.1 Treatment goals in the relapsed setting include delaying symptomatic disease progression and prolonging survival.2 Improvements in overall survival are difficult to demonstrate in ovarian cancer trials because of crossover from the control group to the investigational group and longer post-progression survival associated with post-progression therapies.3, 4 The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is approved in many countries as maintenance therapy for patients with platinum-sensitive, relapsed ovarian cancer, regardless of BRCA1 or BRCA2 (BRCA1/2) mutation status.5, 6, 7, 8 Olaparib is also approved as maintenance therapy in the newly diagnosed ovarian cancer setting.5, 6, 9, 10 In the primary analysis of the phase 3 trial, median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p<0·0001) in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation.11 Olaparib tablets had a manageable toxicity profile, and did not have a significant detrimental effect on health-related quality of life compared with the matched placebo.11, 12 At the primary analysis, overall survival data were immature. In this final analysis we report the mature overall survival results, updated results for other secondary efficacy endpoints, and long-term safety data of maintenance olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation.

Research in context

Evidence before this study

We searched PubMed using the search terms “poly (ADP-ribose) polymerase inhibitor” or “PARP inhibitor”, “ovarian cancer”, “maintenance”, and “platinum-sensitive relapsed”, using no date or language restrictions. The phase 2 Study 19 trial showed an apparent overall survival benefit with maintenance olaparib capsules versus placebo in the subgroup of patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation.

Added value of this study

To our knowledge, olaparib is the only poly (ADP-ribose) polymerase (PARP) inhibitor with long-term follow-up data and SOLO2 is the first phase 3 trial that provides final overall survival data on maintenance therapy with a PARP inhibitor (olaparib) in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Improvements in overall survival are difficult to demonstrate in ovarian cancer trials because of crossover and use of post-progression therapies. However, this analysis showed an overall survival improvement of 12·9 months with maintenance olaparib compared with placebo, although this finding was not statistically significant.

Implications of all the available evidence

Patients with relapsed ovarian cancer are a challenging population to treat, and usually receive multiple lines of chemotherapy, with time to relapse typically shortening with each successive line of treatment. Prior to this analysis, little progress had been made in demonstrating overall survival improvements in ovarian cancer since the introduction of platinum-based chemotherapy. The final analysis of SOLO2 shows a clinically meaningful overall survival benefit of maintenance olaparib for patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation, although the predefined threshold for statistical significance was not met.

Section snippets

Study design and participants

This international, randomised, double-blind, placebo-controlled, phase 3 trial (SOLO2/ENGOT-Ov21) was done by the European Network for Gynaecological Oncological Trial groups (ENGOT) using ENGOT Model C,13 across 123 medical centres in 16 countries (appendix pp 3–4). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer,

Results

Between Sept 3, 2013, and Nov 21, 2014, 602 patients were screened for eligibility, of whom 295 (49%) were enrolled and randomly assigned (196 [66%] to olaparib and 99 [34%] to placebo; figure 1). 195 (99%) of 196 patients assigned to olaparib received olaparib; one ineligible patient was randomly assigned in error and did not receive olaparib. Final data cutoff was on Feb 3, 2020.

Baseline characteristics were well balanced between the two groups (table 1). A confirmed Myriad germline BRCA1/2

Discussion

In the SOLO2 trial of patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation, who had received at least two previous lines of platinum-based chemotherapy, median overall survival with maintenance olaparib was 51·7 months (95% CI 41·5–59·1) when measured from randomisation at the end of chemotherapy; this duration of overall survival is longer than previously reported in platinum-sensitive, relapsed ovarian cancer trials of chemotherapy or chemotherapy plus bevacizumab,

Data sharing

Data underlying the findings described in this manuscript can be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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