Elsevier

The Lancet

Volume 390, Issue 10106, 28 October–3 November 2017, Pages 1949-1961
The Lancet

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

https://doi.org/10.1016/S0140-6736(17)32440-6Get rights and content

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 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.

Introduction

Ovarian cancer is the eighth-leading cause of death from cancer in women worldwide.1 Most patients with advanced-stage ovarian carcinoma initially receive platinum-based chemotherapy and achieve a clinical response; however, most of these patients will ultimately relapse.2 Treatment for initial recurrent disease depends on many factors, including duration of initial treatment response, antecedent and persistent adverse events, performance status, histology, location and burden of disease, and, increasingly, tumour genomics, such as BRCA mutation status.3 For patients with platinum-sensitive recurrent ovarian carcinoma, maintenance treatment with targeted agents has resulted in greater prolongation of progression-free survival than without this treatment.4, 5, 6, 7, 8, 9 However, clinical benefit is typically transient, hence the pursuit continues for new therapies and tools to identify patients who might benefit most from these therapies, as well as to identify the optimal therapeutic strategy.

The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is approved in the USA for treatment of patients with deleterious BRCA mutation (germline or somatic)-associated advanced ovarian carcinoma who have received two or more chemotherapy regimens. Approval of rucaparib was based on the proportion of patients with an objective response (57 [54%] of 106 patients) observed in a pooled population of patients with BRCA-mutant high-grade ovarian carcinoma from the Study 1010 and ARIEL211 clinical trials.

In part 1 of the ARIEL2 trial,11 rucaparib treatment was found to be efficacious not only in patients with relapsed, platinum-sensitive, high-grade ovarian carcinoma with a BRCA mutation, but also in those with BRCA wild-type carcinomas with high genomic loss of heterozygosity (LOH), a potential marker of homologous recombination deficiency (HRD) and thus PARP inhibitor activity.12, 13, 14, 15 The next-generation sequencing (NGS) assay used in ARIEL2 combines mutation analysis of BRCA1 and BRCA2 genes with measurement of the percentage of genome-wide LOH in the cancer tissue as a biomarker for sensitivity to rucaparib treatment. In this randomised, double-blind, placebo-controlled, phase 3 trial (ARIEL3), our objective was to assess the efficacy and safety of rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, platinum-sensitive ovarian carcinoma (including fallopian tube and primary peritoneal carcinomas) and prospectively test the genomic LOH cutoff discriminator that was optimised on the basis of results of ARIEL2 part 1 as a predictive biomarker for sensitivity to rucaparib treatment.

Section snippets

Study design and patients

In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres in Australia, Belgium, Canada, France, Germany, Israel, Italy, New Zealand, Spain, the UK, and the USA. Eligible patients were aged 18 years or older, had platinum-sensitive (ie, documented radiological disease progression more than 6 months after the last dose of the penultimate platinum administered), high-grade serous or endometrioid ovarian, primary peritoneal, or

Results

Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo (figure 1, figure 2). At the visit cutoff date (April 15, 2017), 90 (24%) patients in the rucaparib group and nine (5%) in the placebo group were still receiving treatment. Baseline characteristics were generally well balanced between the treatment groups (table 1).

Following the ordered step-down multiple comparisons procedure, we evaluated investigator-assessed

Discussion

Rucaparib maintenance treatment significantly improved progression-free survival compared with placebo in all primary analysis groups of patients with recurrent ovarian carcinoma after a complete or partial response to platinum-based therapy, as well as when assessed by the BICR and across all prespecified subgroups. Analysis of non-nested, non-overlapping patient subpopulations indicate that the significant improvement in progression-free survival observed in the intention-to-treat population

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