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Clinical Trial
. 2025 May;132(8):725-732.
doi: 10.1038/s41416-025-02966-x. Epub 2025 Mar 17.

Overall survival with maintenance olaparib in platinum-sensitive relapsed ovarian cancer by somatic or germline BRCA and homologous recombination repair mutation status

Sandro Pignata  1 , Amit Oza  2 , Geoff Hall  3 , Beatriz Pardo  4 , Radoslaw Madry  5 , David Cibula  6 , Jaroslav Klat  7 , Ana Montes  8 , Rosalind Glasspool  9 , Nicoletta Colombo  10 , Imre Pete  11 , Ana Herrero Ibáñez  12 , Margarita Romeo  13 , Rumyana Ilieva  14 , Constanta Timcheva  15 , Massimo Di Maio  16 , Zahid Bashir  17 , Rosie Taylor  18 , Alan Barnicle  19 , Andrew Clamp  20
Affiliations
Clinical Trial

Overall survival with maintenance olaparib in platinum-sensitive relapsed ovarian cancer by somatic or germline BRCA and homologous recombination repair mutation status

Sandro Pignata et al. Br J Cancer. 2025 May.

Abstract

Background: The open-label, single-arm, multicentre ORZORA trial (NCT02476968) evaluated maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) with a germline (g) or somatic (s) BRCA1 and/or BRCA2 mutation (BRCAm) or a non-BRCA homologous recombination repair mutation (non-BRCA HRRm).

Methods: Patients were in response to platinum-based chemotherapy after ≥2 prior lines of treatment and underwent prospective central screening for tumour BRCA status, then central gBRCAm testing to determine sBRCAm or gBRCAm status. An exploratory cohort evaluated non-BRCA HRRm in 13 predefined genes. Patients received olaparib 400 mg (capsules) twice daily until investigator-assessed disease progression. Secondary endpoints included overall survival (OS) and safety.

Results: 177 patients received olaparib. At the final data cutoff (25 June 2021), median OS from study enrolment was 46.8 (95% confidence interval [CI] 37.9-54.4), 43.2 (31.7-NC [not calculated]), 47.4 (37.9-NC) and 44.9 (28.9-NC) months in the BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts, respectively. No new safety signals were identified.

Conclusion: Maintenance olaparib showed consistent clinical activity in the BRCAm and sBRCAm cohorts; exploratory analysis suggested similar activity in the non-BRCA HRRm cohort. These findings highlight that patients with PSR OC, beyond those with gBRCAm, may benefit from maintenance olaparib.

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Conflict of interest statement

Ethics approval and consent to participate: The trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines and the AstraZeneca policy of bioethics ( https://www.astrazeneca.com/content/dam/az/PDF/2019/Bioethics%20Policy%20final.pdf ) was approved by the Ethics Committee of Istituto Nazionale Tumori ‘Fondazione G Pascale’ (Reference no. 25/15). All patients provided written informed consent. Competing interests: Sandro Pignata: Honoraria from AstraZeneca, Merck Sharp & Dohme (MSD), Roche, Pfizer, GlaxoSmithKline (GSK) and Clovis Pharma; and research funding from Roche, MSD, AstraZeneca and Pfizer. Amit Oza: Principal investigator of investigator-initiated studies with AstraZeneca; institutional grant funding from AstraZeneca; and steering committee member (non-compensated) for AstraZeneca, Clovis Oncology and GSK. Geoff Hall: Research funding from IQVIA. Beatriz Pardo: Research funding from AstraZeneca, GSK, Clovis and MSD. Radoslaw Madry: Advisory board participation for AstraZeneca, Roche and GSK; and personal fees from AstraZeneca, Roche and GSK. David Cibula: Advisory board participation for AstraZeneca, Roche, Genmab, SOTIO, Merck and GSK. Jaroslav Klat: Reports no disclosures. Ana Montes: Reports no disclosures. Rosalind Glasspool: Principal investigator for trials sponsored by AstraZeneca, Clovis, Tesaro, Immunogen, Pfizer and Lilly; research funding from Clovis, Boehringer Ingelheim and Lilly/Ignyta; institution research funding from Tesaro; institutional fees from Novartis; and personal fees from AstraZeneca, MSD, Clovis, Tesaro, GSK, Immunogen and SOTIO. Nicoletta Colombo: Personal fees from AstraZeneca, MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, BIODCAD and Immunogen. Imre Pete: Reports no disclosures. Ana Herrero Ibáñez: Consulting/advisory board participation for GSK; speakers’ bureau participation for Clovis, GSK, MSD, PharmaMar; and research funding from AstraZeneca and Roche. Margarita Romeo: Institution research funding from AstraZeneca, GSK, Clovis and Pfizer; personal fees from MSD and GSK; and AstraZeneca employment (this author became an AstraZeneca employee in July 2024; her contributions to this manuscript were made while working at her previous institution). Rumyana Ilieva: Reports no disclosures. Constanta Timcheva: Principal investigator of clinical trials of AstraZeneca, Roche, Novartis, Pfizer and Merck; and member of advisory boards of Astellas, Servier and Novartis. Massimo Di Maio: Principal investigator of clinical trials of Roche, Merck, BeiGene, Novartis, Pfizer and Exelixis; member of advisory boards of AstraZeneca, Roche, Novartis, Pfizer, Eisai, Astellas, Janssen, Merck and Amgen; and institutional research funding from GSK/Tesaro. Zahid Bashir: AstraZeneca employment (at time of study); and stock ownership of Omniac Pharm Consult Ltd. Rosie Taylor: AstraZeneca employment and stock ownership. Alan Barnicle: AstraZeneca employment and stock ownership. Andrew Clamp: Research funding from AstraZeneca; and honoraria from AstraZeneca, Clovis Oncology, GSK/Tesaro and Eisai.

Figures

Fig. 1
Fig. 1. Frequency of non-BRCA HRR gene mutations in ORZORA [14].
In addition to the non-BRCA HRR gene mutations shown, non-BRCA HRR gene mutations with a prevalence of 0% included: BARD1, CHEK1, CHEK2, PPP2R2A, RAD51B and RAD54L. *Co-occurring genes included CHEK2 and RAD51C. HRR homologous recombination repair.
Fig. 2
Fig. 2. Kaplan–Meier plots of overall survival.
Overall survival in patients with a BRCAm and b an sBRCAm, gBRCAm or non-BRCA HRRm. BRCAm BRCA1 and/or BRCA2 mutation, CI confidence interval, gBRCAm germline BRCAm, HRRm homologous recombination repair mutation, NC not calculated, OS overall survival, sBRCAm somatic BRCAm.
Fig. 3
Fig. 3. Swimmer plot of patient-level overall survival in the non-BRCA HRR mutation cohort.
*Patient censored on Day 1 had a CDK12 mutation. HRR homologous recombination repair.
See this image and copyright information in PMC

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