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