Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial

Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.