Relevance of Platinum-free Interval and <i>BRCA</i> Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for g<i>BRCA</i> Advanced Breast Cancer (BROCADE3 Crossover).

Abstract

Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (g<i>BRCA</i>)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Eligible patients (<i>N</i> = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300-400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. <i>BRCA</i> reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA). Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with <180 days [responses in 23.1% (3/13) vs. 13.5% (5/37) of patients]. <i>BRCA</i> reversion mutations that restored protein function were detected in ctDNA from 4 of 28 patients tested, and the mean duration of crossover veliparib monotherapy was <1 month in these 4 patients versus 7.49 months in patients lacking reversion mutations. The most frequent adverse events were nausea (61%), vomiting (29%), and fatigue (24%). Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. <i>BRCA</i> reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.