BROCADE study: adding the PARP inhibitor veliparib to chemotherapy significantly improves overall response rate in BRCA mutant breast cancer
Adding the investigational oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor veliparib to chemotherapy significantly improved the overall response rate without increasing adverse events among patients with locally recurrent or metastatic BRCA-mutant breast cancer, according to data from the phase II BROCADE trial. PARP inhibitors block DNA damage repair and may thereby enhance the clinical activity of chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Preclinical studies have shown that PARP inhibition enhances the antitumor activity of platinum agents.
In BROCADE, a randomised, placebo controlled phase II trial, 290 patients with BRCA1 or BRCA2 mutations were randomised to three arms: veliparib (120 mg BID D 1-7) plus carboplatin (AUC6, D3) and paclitaxel (175 mg/m2, D3, 21-D cycle) (N=97), placebo (BID D 1-7) plus carboplatin and paclitaxel (N=99), and veliparib (40 mg BID D1-7) plus temozolomide (28-D cycle) (N=94). Patients who were randomised were 18 years of age or older, had a deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. During the SABCC 2016 congress, dr. Heather Han presented the data from the patients in the carboplatin and paclitaxel with veliparib or placebo-arms.
More than half of the patients in these arms had hormone receptor-positive breast cancer. About 40% had triple-negative breast cancer, and a few had HER2-positive breast cancer. Patients assigned to placebo, carboplatin, and paclitaxel received a median of 10 cycles, compared to a median of 12 treatment cycles for patients in the veliparib plus carboplatin and paclitaxel arm.
The primary endpoint was progression-free survival (PFS) per RECIST 1.1. Analysis at the 112th PFS event in the veliparib and placebo arms showed an improvement in PFS in the veliparib arm (14.1 months versus 12.3 months in the placebo arm), which was not statistically significant (HR [95% CI] 0.789 [0.536-1.162], p=0.231). The trend to improved overall survival (OS) was also not statistically significant (28.3 months versus 25.9 months respectively). The overall response rate for the veliparib arm was 77.8% compared to 61.3% for the placebo arm (p=0.027).
There was no significant increase in toxicity with the addition of veliparib to chemotherapy. The most common grade 3 or higher adverse events were neutropenia (56% in patients assigned to veliparib compared to 55% of patients in the placebo arm), and thrombocytopenia (31% versus 26%). The main limitation of the study was that the number of patients was not sufficient to power the study to detect nondramatic improvements in PFS, according to the authors. However, an ongoing phase III trial will have the power to address this issue.
In summary, the addition of veliparib to chemotherapy significantly improved the overall response rate among patients with BRCA-mutated breast cancer, while the toxicity of the treatment was not increased. Although the improvements in PFS and OS were not statistically significant, the study supports further investigation of veliparib in combination with chemotherapy as a potential treatment for this group of patients.;
Han HS, Diéras V, Robson ME, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. San Antonio Breast Cancer Symposium 2016, abstract S2-05.