Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge.

PATIENTS AND METHODS

This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint.

RESULTS

Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge.

CONCLUSIONS

In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure EPL reports lecture fees, fees for serving on a speakers bureau, and travel support from AstraZeneca, GSK, Roche, and Tesaro; lecture fees from Clovis Oncology and Pfizer; expert testimony fees from AstraZeneca; support for attending meetings and/or travel from AstraZeneca and GSK; fees from AstraZeneca, Incyte, and Roche for participating on a data safety monitoring board or advisory board; and employment by ARCAGY Research. FS reports institutional research funding from AstraZeneca, Agenus, GSK/Tesaro, Immunogen, Incyte, MSD, and Roche; and honoraria from AstraZeneca, Clovis Oncology, GSK/Tesaro, MSD, and Sandoz (Novartis). GS reports grant/research support from MSD Italia S.r.l.; consulting fees from Johnson & Johnson and Tesaro Bio Italy S.r.l.; and speakers bureau fees/honoraria from Clovis Oncology Italy S.r.l. and MSD Italia Srl. BA reports honoraria from BMS, AstraZeneca, Roche, Daiichi, Servier, and Pierre Fabre. FM reports support for the present manuscript from AstraZeneca; grants or contracts to their institution from AstraZeneca, Clovis, Gilead Sciences, GSK/Tesaro, MSD, Novartis, Roche, and Vaccibody; personal consulting fees from AstraZeneca, Eisai, Genomic Health, GSK/Tesaro, and Pfizer; consulting fees to their institution from Vaccibody; personal/institutional consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Agendia, AstraZeneca, Clovis, Eli Lilly, Eisai, Genomic Health, GSK/Tesaro, Immunomedics/Gilead, MSD, Myriad Genetics, Novartis, Pfizer, PharmaMar, Pierre Fabre, Roche, and Seattle Genetic; support for attending meetings and/or travel from AstraZeneca, Pfizer, and Roche; and participation on a data safety monitoring board or advisory board for Palleos. KL reports support for the present manuscript from AstraZeneca and Merck; grants to their institution from GSK; consulting fees to their institution from AstraZeneca; fees paid to their institution for participation on a data safety monitoring board or advisory board from AstraZeneca, MSD, and Eisai; and being the deputy director of the Nordic Society of Gynecologic Oncology (NSGO) and on the advisory group to the Cancer Registry of Norway cervical cancer reference group. NC reports grants from AstraZeneca, PharmaMar, and Roche; honoraria for lectures from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tesaro; honoraria for advisory boards from AstraZeneca, BioCad, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Nuvation Bio, OncXerna, Pfizer, PharmaMar, Roche, and Tesaro; and being a steering committee member on European Society for Medical Oncology (ESMO) clinical guidelines and a scientific committee chair for Acto Onlus. RM reports serving on advisory boards with AstraZeneca, Roche, and GSK; and personal fees from AstraZeneca, Roche, and GSK. RG reports support for the present manuscript from AstraZeneca/MSD, including institutional funding for the conduct of the trial; funding for an investigator-initiated study from Clovis Oncology, Boehringer Ingelheim, and Lilly/Ignyta; personal consultancy/advisory board fees from GSK and Clovis Oncology and institutional fees for a trial steering committee from Novartis; honoraria for lectures and educational reports from GSK, honoraria for lectures from Clovis Oncology, and honorarium for educational events from AstraZeneca; virtual meeting registration fees from GSK; participation on an independent data monitoring committee for the MATAO trial; being an International Gynecologic Cancer Society (IGCS) council member and advocacy committee chair elect, and Past Chair of the Gynecologic Cancer InterGroup (GCIG) meta-analysis committee; being Chair of the Scottish Gynaecological Cancer Trials Group (SGCTG) and ovarian cancer workstream committee member of the National Cancer Research Institute (NCRI); and that their institution received niraparib on a drug donation scheme from GSK. IV reports grants or contracts (corporate-sponsored research) from Amgen and Roche; grants or contracts (contracted research via KULeuven) from Oncoinvent AS and Genmab; consulting fees from Aksebio, Amgen (Europe) GmbH, AstraZeneca, Bristol Myers Squibb, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffman-La Roche Ltd., Genmab, GSK, Immunogen Inc., Jazz Pharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AZ, Seagen, Sotio a.s., Verastem Oncology, and Zentalis; and support for attending meetings and/or travel from Amgen, AstraZeneca, MSD, Roche, and Tesaro. SL reports support for the present manuscript from AstraZeneca; grants or contracts to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare, GSK, and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GSK, Eisai, and Shattuck Labs; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Eisai; and participation on a data safety monitoring board or advisory board from AstraZeneca. CD reports participation on a data safety monitoring board or advisory board for MSD, Eisai, and AstraZeneca. AO reports grants to their institution from AbbVie Deutschland GmbH & Co. Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, Beigene USA, Inc., Belgian Gynaecological Oncology Group (BGOG), Bristol Myers Squibb International Corporation, Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche Ltd., Grupo Español de Investigación en Cáncer de Ovario (GEICO), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Sharp & Dohme, Millennium Pharmaceuticals, Mundipharma Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Clovis Oncology, Deciphera Pharmarceuticals, Genmab, GSK, Immunogen, Mersana Therapeutic, PharmaMar, Roche, Sutro, and Tesaro; support for attending meetings and/or travel from AstraZeneca, PharmaMar, and Roche; and participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, Roche Farma, Sattucklabs, and Sutro Biopharma, Inc. CZ reports grants or contract to self from Amgen, Celgene, Daiichi, Eisai, Eli Lilly, GSK, MSD, and PharmaMar; grants or contract to self and institution from AstraZeneca, Instituto Gentili, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Tesaro, and Teva; support for attending meetings and/or travel from Celgene, Instituto Gentili, Novartis, Pfizer, PharmaMar, Pierre Fabre, Roche, and Tesaro; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Celgene, Daiichi, Eisai, Eli Lilly, GSK, MSD, Novartis, Pfizer, PharmaMar, QuintilesIMS, Roche, and Tesaro; and other financial or non-interests for Amgen, AstraZeneca, Daiichi, GSK, MSD, Novartis, Pfizer, PharmaMar, QuintilesIMS, Roche, and Tesaro. FH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amedes, AstraZeneca, Clovis, GSK, Novocure, PharmaMar, Roche, and Tesaro; participation on a data safety monitoring board or advisory board for Amedes, AstraZeneca, Clovis, GSK, Roche, and Tesaro; and leadership or fiduciary role in the AGO study group. LG reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Clovis, Eisai, GSK, and MSD; and participation on an advisory board for AstraZeneca, GSK, and MSD. PS reports honoraria from GSK. CB reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. BS reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. IR-C reports grants to self from BMS, MSD, and Roche; grants to their institution from AstraZeneca, BMS, Merck Serono, MSD, Novartis, and Roche; consulting fees from AstraZeneca, Agenus, Advaxis, Amgen, BMS, Clovis, Deciphera, Genmab, GSK, Mersana, Merck Serono, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, and Tesaro; payment or honoraria to self for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Agenus, Advaxis, Amgen, AstraZeneca, BMS, Clovis, Deciphera, Genmab, GSK, Mersana, Merck Serono, MSD, Novartis, Pfizer, PharmaMar, Roche, and Tesaro; payment or honoraria to institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, GSK, MSD, and Roche; and support for attending meetings and/or travel from AstraZeneca, GSK, and Roche. AR reports consulting fees from AstraZeneca, Clovis, GSK, MSD, and PharmaMar; payment or honoraria to self for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Clovis, GSK, MSD, and PharmaMar; and support for attending meetings and/or travel from AstraZeneca, Clovis, and PharmaMar. All other authors have declared no conflicts of interest.