Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis

A Poveda,S Lheureux,N Colombo,D Cibula,K Lindemann,J Weberpals,M Bjurberg,A Oaknin,M Sikorska,A González-Martín,R Madry,M.J Rubio Pérez,J Ledermann,R Davidson,C Blakeley,J Bennett,A Barnicle,E Škof

doi:10.1016/j.ygyno.2021.12.025

Abstract

ObjectiveThe phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. MethodsIn this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. ResultsTwo hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6–10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. ConclusionMaintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.

Highlights

The treatment goals of relapsed ovarian cancer include delaying symptomatic disease progression, postponing the need for subsequent chemotherapy with its associated toxicities, and prolonging survival [1]
homologous recombination deficiency (HRD) can be determined by germline or somatic mutation screening of genes involved in homologous recombination repair, or by measuring genomic instability via assays that can evaluate loss of heterozygosity (LOH), telomeric allelic imbalance, and largescale state transitions [4,5,6]
Planned exploratory endpoints assessed at the primary analysis included investigator-assessed progression-free survival (PFS) by the number of prior platinumbased chemotherapy regimens (2 vs. >2), objective response to latest platinum-based chemotherapy (CR/no evidence of disease (NED) vs. partial response (PR)), and by age at enrollment (

Summary

Introduction

The treatment goals of relapsed ovarian cancer include delaying symptomatic disease progression, postponing the need for subsequent chemotherapy with its associated toxicities, and prolonging survival [1]. Treatment aims to control disease symptoms and maintain patient quality of life. Double-strand breaks cannot be accurately repaired in tumors with homologous recombination deficiency (HRD), such as those with BRCA1 and BRCA2 (BRCA) mutation, as error-prone pathways (primarily non-homologous end joining) lead to chromosomal instability and tumor cell death [2,3]. HRD can be determined by germline or somatic mutation screening of genes involved in homologous recombination repair, or by measuring genomic instability via assays that can evaluate loss of heterozygosity (LOH), telomeric allelic imbalance, and largescale state transitions [4,5,6]

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Conclusion