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

Abstract

Summary 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...

ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

“…The latter group included patients with a somatic BRCA mutation or BRCA WT 38. In ARIEL3,37 rucaparib given after a response to platinum-based therapy showed similar results in patients with BRCA mutations (germline or somatic mutations) as well as in the whole ITT group with high-grade cancer. Both NOVA and ARIEL3 trials included tumour testing for HRD, but neither was able to exclude a benefit from PARP inhibitors in HRD-negative patients.…”

“…However, attempts to use LOH as a predictive marker in the maintenance setting were less successful. The ARIEL3 study37 evaluated rucaparib versus placebo as maintenance treatment in patients with recurrent platinum-sensitive cancer and found rucaparib maintenance treatment significantly improved PFS versus placebo in the nested BRCA -mutated and HR deficiency (HRD) cohorts and in the overall intention-to-treat (ITT) population. PFS was improved with rucaparib maintenance treatment versus placebo in patients with BRCA WT EOC (LOH high and LOH low) as well.…”

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

“…This goal was addressed by using CRISPR/Cas9 to delete PARP1 in models of ovarian cancer, which were then used to test PARPi efficacy in vitro. In addition, we used patient-derived orthotopic xenograft models of ovarian cancer to show proof of concept for [ 18 F]FTT microPET imaging of PARP-1 and PARPi drug-target engagement in less of BRCA mutation status (6)(7)(8). These clinical reports suggest there is a need for predictive biomarkers for PARPi therapy that go beyond BRCA mutation and HRD testing.…”

PARP inhibitors for homologous recombination-deficient prostate cancer

“…[64] Niraparib and rucaparib maintenance therapy have also shown promise for recurrent ovarian carcinoma although in distinction the demonstrated benefit occurs in patients irrespective of the presence or absence of a germline BRCA mutation. [65, 66]…”