Abstract LB-A12: Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma
Authors: O'Malley David M. , Coleman Robert L. , Oza Amit M. , Lorusso Domenica , Aghajanian Carol , Oaknin Ana , Dean Andrew , Colombo Nicoletta , McNeish Iain A. , Swisher Elizabeth M. , Scott Clare L. , Konecny Gottfried E. , Giordano Heidi , Cameron Terri , Maloney Lara , Goble Sandra , Sun James , Harding Thomas C. , Lin Kevin K. , Ledermann Jonathan A. 
Published: August 2018

Background: High-grade ovarian carcinomas (HGOC) with a mutation in BRCA1/2 or other core homologous recombination repair (HRR) genes are sensitive to treatment with the PARP inhibitor rucaparib. To study whether HRR gene mutations confer sensitivity to rucaparib in the maintenance setting, we performed next-generation sequencing (NGS) on carcinomas from a double-blind, placebo-controlled, phase 3 study of rucaparib in patients with HGOC following response to platinum-based chemotherapy (ARIEL3, NCT01968213). Materials and Methods: Archival ovarian carcinoma specimens were required for all 564 patients who were randomized in ARIEL3 and were sequenced using Foundation Medicine’s NGS-based assay to identify deleterious mutations in a prespecified list of HRR genes (BRCA1/2 and 28 non-BRCA HRR genes, including ATM, BARD1, BRIP1, CHEK2, RAD51C, RAD51D, RAD54L, and FANC family genes). Patients were randomized 2:1 to receive oral rucaparib 600 mg twice daily or placebo. The randomization was stratified by HRR gene mutation status (BRCA, non-BRCA HRR, no mutation in BRCA or HRR gene), progression-free interval of the penultimate platinum-based regimen, and best response to most recent platinum regimen. The primary endpoint for ARIEL3 was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Exploratory analysis of confirmed response was conducted for the subgroup of patients with measurable disease at study entry. Results: Deleterious mutations in non-BRCA HRR genes were detected in ovarian carcinoma specimens from 7.6% (43/564) of randomized patients. In these patients, PFS was significantly longer with rucaparib than with placebo (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.50; P=0.0005), with a median PFS of 11.1 mo and 5.5 mo, respectively. This HR is similar to that found in women with carcinomas containing a BRCA1/2 mutation (0.23; 95% CI, 0.16-0.34). The most commonly found non-BRCA HRR gene mutations among the 28 patients in the rucaparib arm were RAD51C (n=6) and RAD51D (n=4) and among the 15 patients in the placebo arm were BRIP1 (n=5) and RAD51C (n=2). A diverse set of mutation types were detected, including frameshift insertions/deletions, homozygous deletions, and nonsense and splice site mutations. All 10 RAD51C/D mutations were homozygous within the carcinomas, indicating biallelic loss. Additionally, all RAD51C/D-mutant carcinomas exhibited high genomic loss of heterozygosity, which is a type of genomic scar characteristic of HRR deficiency. At the visit cutoff date (15 April 2017), only 2 of the 10 RAD51C/D cases in the rucaparib arm had disease progression; 7 had a PFS duration of at least 1 y (median PFS, 16.4 mo; range 5.4+ to 30.4+ mo). Three of the RAD51C/D cases were in the subgroup of patients who had measurable disease at baseline, and all achieved a confirmed response (1 complete response and 2 partial responses). In comparison, the 3 RAD51C/D cases in the placebo arm had a median PFS of 5.4 mo (range, 3.9 to 5.5 mo). Conclusions: Patients with recurrent platinum-sensitive HGOC harboring a deleterious mutation in non-BRCA HRR genes (including RAD51C/D) had significantly longer PFS with rucaparib maintenance treatment than with placebo.

Citation Format: David M. O'Malley, Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Iain A. McNeish, Elizabeth M. Swisher, Clare L. Scott, Gottfried E. Konecny, Heidi Giordano, Terri Cameron, Lara Maloney, Sandra Goble, James Sun, Thomas C. Harding, Kevin K. Lin, Jonathan A. Ledermann. Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A12.