LBA9 - Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer

BRCA-mutated tumors are susceptible to both platinum and PARP inhibitors due to deficiency in homologous recombination repair. Veliparib (Vel) is a PARP1/2 inhibitor with antitumor activity and acceptable toxicity as a single-agent or combined with carboplatin and paclitaxel (C/P) in pts with BRCA mutated breast cancer. This double blind, placebo (Pbo)-controlled, phase III trial (NCT02163694) randomized pts 2:1 to C/P with Vel or Pbo. Pts had gBRCA1/2 mutations and ≤2 prior lines of cytotoxic therapy for metastatic breast cancer. Vel (120mg p.o. BID) or Pbo was given on Days −2 to 5 with C (AUC 6, d1) and weekly P (80mg/m2, d1, 8, 15) in 21-d cycles. Pts who discontinued both C and P but had not progressed received blinded single-agent Vel or Pbo (300-400mg BID). Treatment was to progression. Primary endpoint was PFS (per investigator); secondary endpoints included OS, clinical benefit rate, objective response rate, and PFS2. Median age was 47 years (range 24–82), 48% were ER/PgR–, 8% had prior platinum therapy, 4% had history of CNS metastases, and 19% had prior chemotherapy for metastatic disease. Efficacy data are summarized in the Table. Among AEs of special interest (all-grades), neutropenia occurred in 91%/91%, thrombocytopenia in 82%/72%, anaemia in 81%/70%, and nausea and vomiting in 75%/68% of pts in Vel vs Pbo arms, respectively. Most common (≥20%) study drug-related G3+ AEs in Vel and Pbo arms were anaemia (27%/17%), neutropenia (52%/50%), and thrombocytopenia (25%/15%). In Vel vs Pbo arms, 88%/86% had C dose reduction and 74%/70% had P dose reduction.TableLBA9TableEfficacy summaryVeliparib + C/P, n=337Placebo + C/P, n=172mPFS per INV (months, 95% CI)14.5 (12.5, 17.7)12.6 (10.6, 14.4)PFS per INV HR (95% CI); P value0.71 (0.57, 0.88); 0.0023-year PFS rate (%, 95% CI)26 (20, 31)11 (5.8, 17)mPFS per IRC (months, 95% CI)19.3 (16.5, 23.3)13.5 (12.5, 16.3)PFS per IRC HR (95% CI)0.70 (0.54, 0.90)mOS [interim] (months, 95% CI)33.5 (27.6, 37.9)28.2 (24.7, 35.2)OS HR (95% CI); P value0.95 (0.73, 1.2); 0.67CBR at 24 weeks (%)90.7%93.2%ORR (%)75.8%74.1%mPFS2 per INV (months, 95% CI)21.3 (19.8, 25.1)17.4 (16.0, 20.0)PFS2 per INV HR (95% CI)0.76 (0.60, 0.96)mDoR per INV (months, 95% CI)14.7 (12.1, 18.7)11.0 (10.2, 12.3)C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; INV, investigator; IRC, independent review committee; m, median; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival