Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.

Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.

Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9-16·2) versus 5·4 months (5·1-5·6; 0·32 [0·24-0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3-11·4) versus 5·4 months (5·3-5·5; 0·36 [0·30-0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none).

Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy.

Funding: Clovis Oncology.

Conflict of interest statement

Declaration of interests

RLC reports grants from AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, and AbbVie and reports serving as an advisor to AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, Tesaro, GamaMabs, Pfizer, Genmab, Gradalis, Bayer, and AbbVie. AMO has served on advisory boards for Amgen, Verastem, Clovis Oncology, and Immunovaccine; received support for travel or accommodation from AstraZeneca; and received honoraria from WebRx. DL has served in a consulting or advisory role for AstraZeneca, Clovis Oncology, Roche, Tesaro, and PharmaMar and received support for travel or accommodation from Roche and PharmaMar. CA served on a steering committee for Mateon Therapeutics and has served on advisory boards for Clovis Oncology, Cerulean Pharma, Bayer, VentiRx, and AstraZeneca. AO has served on advisory boards for Roche, AstraZeneca, PharmaMar, Clovis Oncology, and Tesaro and received support for travel or accommodation from Roche, AstraZeneca, and PharmaMar. NC has served in a consulting or advisory role for Roche, AstraZeneca, Tesaro, PharmaMar, Clovis Oncology, and Advaxis. JIW has received research support from AbbVie and AstraZeneca and served on advisory boards for AstraZeneca. AC has served on advisory boards for AstraZeneca and Roche and received research support from AstraZeneca. AL has served on an advisory board for Clovis Oncology, Pfizer, and PharmaMar; reports institutional research grant support from GamaMabs and Merus; and reports boarding and travel expenses for congress activities from AstraZeneca. RWH has served on a speakers bureau for AstraZeneca, Clovis Oncology, and Tesaro. PCF has served on advisory boards for Clovis Oncology and AstraZeneca and received honoraria from AstraZeneca. JCG has served on advisory boards for Roche, AstraZeneca, Janssen, Merck, and Bristol-Myers Squibb and received support for travel or accommodation from Roche, Bristol-Myers Squibb, and Astellas. DMO received research funding from Clovis Oncology; received institutional research support from Amgen, VentiRx, Regeneron, Immunogen, Array Biopharma, Janssen, Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, and Genentech/Roche; served on an advisory board for Clovis Oncology, AstraZeneca, Janssen, Genentech/Roche, Eisai, Tesaro, and Novocure; served on steering committees for Amgen, Tesaro, and Novocure; and served as a consultant to Tesaro and Novocure. JG-D has received research funding from AstraZeneca and served on advisory boards for Janssen, Clovis Oncology, and Genentech/Roche. AF has served on advisory boards for AstraZeneca, Roche, and Tesaro. IAM has served on advisory boards for Clovis Oncology, Tesaro, and AstraZeneca. CLS has served in a consulting or advisory role for AstraZeneca, Clovis Oncology, Roche, and Eisai Australia; received support for travel or accommodation from AstraZeneca, Clovis Oncology, and Roche; and received drugs for research from Eisai Australia; and her institution received in kind research support for parallel laboratory work using rucaparib. TC, LM, JI, SG, CG, TCH, KKL, and HG are employees of Clovis Oncology and MR was employed at Clovis Oncology at the time of the study and owns stock in the company. JS is an employee of Foundation Medicine, the developer of the homologous recombination deficiency assay used in this trial. JAL has served in an advisory role for Clovis Oncology and AstraZeneca and served on a speakers bureau for and received research grants from AstraZeneca. All other authors declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile *A full description of protocol deviations is provided in the appendix (p 5); these protocol deviations are reported as of the visit cutoff date (April 15, 2017) and did not result in exclusion of patients or data from any efficacy or safety analyses in the study.

Figure 2

Efficacy analysis cohorts HRD=homologous recombination deficient. ITT=intention-to-treat. LOH=loss of heterozygosity.

Figure 3

Progression-free survival Kaplan-Meier estimates of progression-free survival as assessed by the investigator for patients with a BRCA-mutant carcinoma (A), patients with a homologous recombination deficient carcinoma (B), and the intention-to-treat population (C) and as assessed by the blinded independent central radiology review for patients with a BRCA-mutant carcinoma (D), patients with a homologous recombination deficient carcinoma (E), and the intention-to-treat population (F). Tick marks denote censored patients. HR=hazard ratio.

Figure 4

Progression-free survival in subgroups CA 125=cancer antigen 125. CR=complete response. GCIG=Gynecologic Cancer InterGroup. HR=hazard ratio. LOH=loss of heterozygosity. PR=partial response. RECIST=Response Evaluation Criteria In Solid Tumors. *By local germline testing, central germline testing, or tumour testing. †Tumour sample was not evaluable for percentage of genomic LOH because of low tumour content or aneuploidy. ‡We permitted previous treatment with bevacizumab as part of penultimate or earlier treatment.

Figure 5

Progression-free survival in patients with a BRCA wild-type carcinoma Kaplan-Meier estimates of progression-free survival as assessed by the investigator for patients with a BRCA wild-type carcinoma with high (A) and low (B) loss of heterozygosity. HR=hazard ratio.