Maintenance olaparib prolongs the overall survival of women with platinum-sensitive relapsed ovarian cancer harbouring a BRCA mutation by over 1 year

The final analysis of the randomized phase III SOLO2 trial showed that maintenance olaparib results in a clinically meaningful overall survival (OS) benefit in women with BRCA-mutated platinum-sensitive ovarian cancer. Compared to placebo, maintenance olaparib resulted in a prolongation of the median OS of 12.9 months. Previous analyses of this trial already showed that olaparib maintenance resulted in a progression-free survival (PFS) improvement of 13.6 months. These new SOLO2 data show that olaparib maintenance not only delays disease progression but also improves the survival of women with platinum-sensitive ovarian cancer with BRCA mutations. Importantly, this survival benefit does not come at the cost of a compromised quality of life.

Introduction

Relapsed ovarian cancer is associated with poor outcomes, and treatment goals include delaying symptomatic disease progression and prolonging survival. However, improving the OS proved to be a difficult task in ovarian cancer trials and limited survival progress was made over the last two decades. As ovarian cancer is characterised by genome instability and often has defects in DNA repair pathways, the high mutation rate provides a unique opportunity for targeted therapy treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Following the positive outcome of multiple phase III trials, many countries have approved maintenance therapy with a PARP inhibitor for patients with platinum-sensitive relapsed ovarian cancer, regardless of their BRCA mutation status. One of these studies was SOLO2 and previous reports of this study demonstrated that maintenance olaparib led to an improvement in the median PFS of 13.6 months over placebo (HR: 0.30, p< 0.0001) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation, with a manageable tolerability profile.

The phase III SOLO2 trial evaluated maintenance olaparib in women with relapsed, high-grade serous ovarian cancer (including primary peritoneal or fallopian tube cancer) or endometrioid cancer with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Patients must have responded to their most recent platinum regimen. Eligible patients (N=295) were randomised (2:1) to olaparib 300 mg, twice daily or matching placebo. Randomisation was stratified by response to previous chemotherapy (complete or partial) and by the length of the platinum-free interval (6-12 months or more than 12 months). The primary endpoint of the trial was investigator-assessed PFS, with OS as a key secondary objective. The results of this endpoint were presented at ASCO 2020.

Results

After a median follow up of 65.7 months in the olaparib arm and 64.4 months for placebo, the median OS was 51.7 months in the olaparib arm as compared to 38.8 months in the placebo arm. As such, maintenance olaparib prolonged the median OS of patients with more than 1 year (12.9 months) compared to placebo. This corresponds to a 26% reduced risk of death with maintenance olaparib (HR [95%CI]: 0.74 [0.54-1.00], p= 0.0537). Importantly, this analysis did not adjust for the 39% of placebo patients that crossed over to receive olaparib therapy resulting in an underestimation of the actual survival benefit induced by olaparib. Five years after randomisation, 42% of the patients in the olaparib arm and 33% of the patients in the placebo arm were still alive. In the subgroup of patients with a germline BRCA mutation, the median OS was 52.4 months with olaparib as compared to 37.4 months with placebo (HR [95%CI]: 0.71 [0.52-0.97], p=0.0306). In addition to this, a post-hoc OS sensitivity analysis was performed that corrected for mis stratification at randomisation. In this analysis, the median OS values were 51.7 months and 38.8 months with olaparib and placebo, respectively (HR [95%CI]: 0.70 [0.52-0.96], p= 0.0231).

The most common treatment-emergent adverse events (TEAE) of any grade were nausea, fatigue/asthenia and anaemia. The latter was also the most common grade ≥ 3 TEAE. Adverse events led to dose interruptions in 50% of the olaparib patients and in 19% of the placebo patients. Dose reductions had to be done in 28% of patients on olaparib, as compared to 3% of the placebo patients. Finally, treatment had to be discontinued in 17% of the patients in the olaparib arm and in 3% of the patients in the placebo arm.

Conclusions

SOLO2 is the first randomised, phase III trial that provides final OS data on maintenance treatment with PARP inhibitors. In the final SOLO2 analysis, maintenance with olaparib resulted in a clinically meaningful OS improvement of 12.9 months compared to placebo. At five years, 42% of the patients in the olaparib group were still alive as compared to 33% with placebo, an absolute difference of 9%. These results indicate that maintenance olaparib monotherapy not only delays disease progression but also improves the OS of women with platinum-sensitive ovarian cancer with BRCA mutations.

Reference

Poveda A, Floquet A, Ledermann J, et al. Final overall survival results from SOLO2/ENGOT-ov21: a Phase III trial assessing maintenance olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation. Presented at ASCO 2020; Abstract 6002.