Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial.

BACKGROUND

Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting.

METHODS

In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m

FINDINGS

Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause).

INTERPRETATION

Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma.

FUNDING

Clovis Oncology.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests RK has received institutional funding from Clovis Oncology for this clinical trial; reports clinical trial grants from Merck Sharp & Dohme; has served as a consultant for Basilea Pharmaceutica and Shattuck Pharma; has received honoraria from Clovis Oncology, AstraZeneca, GlaxoSmithKline, and Incyte; received travelling support from AstraZeneca, GlaxoSmithKline, and Sierra Oncology; has served on data safety monitoring boards or advisory boards for Clovis Oncology, AstraZeneca, BeiGene, Eisai, GlaxoSmithKline, Incyte, iTeos Therapeutics, PharmaMar, and Roche. AF is currently at P A Herzen Cancer Research Institute, Moscow, Russia and delcares no competing interests. ACdM has received institutional funding from Clovis Oncology for this cl.inical trial; reports institutional clinical trial grants from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Regeneron, and Roche; has received honoraria for lectures from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Sanofi; has served on advisory boards for AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche. YS has received honoraria from AstraZeneca, Merck Sharp & Dohme, and Roche. NC reports grants from AstraZeneca and Roche; has served as a consultant for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme/Merck, Mersana, Oncxerna, Pfizer, Pharmamar, Roche, Takeda, and Tesaro; has received honoraria from Clovis Oncology, AstraZeneca, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tesaro; received traveling support from Tesaro; and has served on data safety monitoring boards or advisory boards for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme/Merck, Mersana Therapeutics, OncXerna, Pfizer, PharmaMar, Roche, Takeda, and Tesaro. DL has received institutional funding from Clovis Oncology for this clinical trial; reports institutional research grants from Clovis Oncology, GlaxoSmithKline, and Merck Sharp & Dohme; has served as a consultant for Merck Serono and ParmaMar; has served on advisory boards for Amgen, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and PharmaMar; has received travelling support from AstraZeneca, GlaxoSmithKline, PharmaMar, and Roche; has served on data safety monitoring committee for Novartis; and has served on the board of directors for the Gynecological Cancer Academy, the Gynecological Cancer InterGroup, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies. GS reports grants and research support from Merck Sharp & Dohme Italia SRL; has served as a consultant for Tesaro Bio Italy SRL and Johnson & Johnson; and has received honoraria and served on a speakers' bureau for Clovis Oncology Italy SRL. DC has served as a consultant for Akeso Biopharma, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novocure, Roche, Seagen, and SOTIO. DT, KKL, KM, and SG are employees of Clovis Oncology, and have stock and stock options. AMO reports institutional research grants from AstraZeneca; has served on an advisory board (uncompensated) for GlaxoSmithKline; has served on advisory boards and steering committees (uncompensated) for Clovis Oncology and AstraZeneca; and has served as a principal investigator on investigator-initiated trials for Clovis Oncology, AstraZeneca, and GlaxoSmithKline. All other authors declare no competing interests. Authors received writing support from Clovis Oncology during the conduct of the study. RK is currently at the Department of Oncology, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, UK. AL is currently at the Department of Oncology, Almazov National Medical Research Center, Saint Petersburg, Russia. DL is currently at Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy.