Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

Abstract

Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data.

Methods: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213.

Findings: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths.

Interpretation: In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports.

Funding: Clovis Oncology.

Conflict of interest statement

Declaration of interests

JAL has received lecture fees from Clovis Oncology, AstraZeneca, Merck Sharp & Dohme, Pfizer, and Tesaro; served on advisory boards for Clovis Oncology, Artios Pharma, AstraZeneca, Cristal Therapeutics, Merck Sharp & Dohme, Pfizer, Regeneron, Roche, Seattle Genetics, and Tesaro; and received research grants from AstraZeneca and Merck Sharp & Dohme. AMO has served on advisory boards for Clovis Oncology, Amgen, Immunovaccine, and Verastem; received support for travel or accommodation from AstraZeneca; and received honoraria from WebRx. DL has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, and Tesaro, and received support for travel or accommodation from PharmaMar and Roche. CA has served on a steering committee for Clovis Oncology, AbbVie, Genentech, and Mateon Therapeutics; served on advisory boards for Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, and Tesaro; received research grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech; and received honoraria from Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, Mateon Therapeutics, and Tesaro. AO has served on advisory boards for Clovis Oncology, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, and Tesaro; received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and received research grants from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol-Myers Squibb, Eisai, F Hoffmann-La Roche, Regeneron Pharmaceuticals, ImmunoGen, Merck Sharp & Dohme de Espana, Millennium Pharmaceuticals, PharmaMar, and Tesaro. AD has served in a consulting or advisory role for Precision Oncology Australia, Shire Pharmaceuticals, and Specialised Therapeutics Australia. NC has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, BIOCAD, Pfizer, PharmaMar, Roche, and Tesaro. JIW has received research support from AbbVie and AstraZeneca and served on advisory boards for AstraZeneca. ARC has served on advisory boards for AstraZeneca; received research funding from Clovis Oncology and AstraZeneca; and received support for travel and accommodation for congress attendance from Clovis Oncology, AstraZeneca, and Roche. GS has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, PharmaMar, Roche, and Tesaro. AL has served on advisory boards for Clovis Oncology, AstraZeneca, BIOCAD, GamaMabs, Genmab/Seattle Genetics, Merck Sharp & Dohme, Pfizer, PharmaMar, and Tesaro; received support for travel and accommodation from Clovis Oncology, AstraZeneca, Roche, and Tesaro; and reports institutional research grant support from Clovis Oncology, AstraZeneca, GamaMabs, Inivata, Merck Sharp & Dohme, Merus, Sanofi, and Tesaro. RWH has served on speakers bureaus for Clovis Oncology, AstraZeneca, and Tesaro. MAG has served on advisory boards for Clovis Oncology and on speakers bureaus for AstraZeneca, PharmaMar, and Roche. PCF has served on advisory boards for Clovis Oncology and AstraZeneca and received honoraria from AstraZeneca. JCG has served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb and Tesaro; served on speakers bureaus for Ipsen and Merck Sharp & Dohme; and received support for travel or accommodation from Astellas, AstraZeneca, and Bristol-Myers Squibb. DMO has served on advisory boards for Clovis Oncology, AbbVie, AstraZeneca, Eisai, Genentech/Roche, Genelux, Iovance Biotherapeutics, Janssen, Novocure, Regeneron, and Tesaro; has served on steering committees for Clovis Oncology, Agenus, Amgen, and Novocure; has served as a consultant for AbbVie, Ambry, AstraZeneca, Genentech/Roche, Gynecologic Oncology Group Foundation, and Tesaro; has given a presentation on ovarian cancer at the National Comprehensive Cancer Network; and his institution has received research support from Clovis Oncology, AbbVie, Agenus, Amgen, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, ERGOMED Clinical Research, Genentech, Gynecologic Oncology Group, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen Research and Development, Ludwig Institute for Cancer Research, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, TRACON Pharmaceuticals, VentiRx, Yale University. DKA has served as a scientific advisor for Morphotek and received research funding from Clovis Oncology, Advaxis, AstraZeneca, Pfizer, Syndax, and Tesaro. SB has served on advisory boards and received honoraria from Clovis Oncology, AstraZeneca, PharmaMar, Seattle Genetics, and Tesaro; received honoraria from Merck Serono and Roche; and received support for travel or accommodation from NuCana and Tesaro. JG-D has received research funding from AstraZeneca, Pierre Fabre, and Pfizer; received personal fees from Clovis Oncology, Astellas, Pierre Fabre, and Pfizer; and received nonfinancial support from Astellas, Pierre Fabre, and Pfizer. EMS declares no competing interests. TC, LM, and SG are employees of Clovis Oncology and may own stock or have stock options in that company. RLC reports grants from Clovis Oncology, AstraZeneca, Gateway Foundation, Janssen, Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund, Merck, National Institutes of Health, Roche/Genentech, and V-Foundation; has served as an advisor to Clovis Oncology, Agenus, AstraZeneca, GamaMabs, Genmab, Janssen, OncoQuest, Pfizer (Medivation), Regeneron, Roche/Genentech, and Tesaro; and has an endowment as the Ann Rife Cox Chair in Gynecology. All support from Clovis Oncology reported here was received outside of the submitted work or conduct of the study.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. ARIEL3 populations

Adapted from Coleman et al by permission of Elsevier. HRD=homologous recombination deficient. ITT=intention to treat. LOH=loss of heterozygosity.

Figure 2:. Kaplan–Meier estimates of CFI, TFST, PFS2, and TSST in the ITT population

The ITT population consisted of 375 patients in the rucaparib group and 189 patients in the placebo group. CFI=chemotherapy-free interval. HR=hazard ratio. ITT=intention to treat. PFS2=time to disease progression on subsequent therapy or death. TFST=time to start of first subsequent therapy. TSST=time to start of second subsequent therapy.

Figure 3:. First and second subsequent lines of therapy for the ITT population

Visit cutoff Dec 31, 2017. ITT=intention to treat. PARP=poly(ADP-ribose) polymerase. VEGF=vascular endothelial growth factor. *Eligible patients who discontinued from ARIEL3; excludes 21 patients from the rucaparib group and nine patients from the placebo group who withdrew consent during treatment or follow-up. †Eligible patients who discontinued from ARIEL3; excludes 23 patients from the rucaparib group and 11 patients from the placebo group who withdrew consent during treatment or follow-up. ‡As first subsequent therapy, three patients received olaparib plus cediranib (rucaparib: n=1; placebo: n=2), two received olaparib plus durvalumab (placebo: n=2), and one received olaparib plus radiotherapy (rucaparib: n=1); as second subsequent therapy, one patient received olaparib plus cediranib (rucaparib: n=1) and one received olaparib plus vistusertib (placebo: n=1). §Other treatment includes VEGF inhibitor, hormonal therapy, immunotherapy, investigational treatment (unspecified), radiation, and hyperthermic intraperitoneal chemotherapy. ¶Patient might not have started any subsequent treatment as of the visit cutoff or was transferred to palliative care.