The trial did not meet the primary endpoint, but we think the trend toward improved progression-free survival and overall survival is encouraging.— Hyo Sook Han, MD
A randomized phase II study in women with metastatic breast cancer who have mutations in BRCA1 or BRCA2 evaluated the addition of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to combination chemotherapy. The trial did not meet its primary endpoint.1 Hyo Sook Han, MD, of Moffitt Cancer Center in Tampa, Florida, reported at the 2016 San Antonio Breast Cancer Symposium: “The addition of veliparib to carboplatin/paclitaxel resulted in trends toward improved progression-free survival and overall survival and a significant increase in objective response rate."
Median progression-free survival was 12.3 months with carboplatin/paclitaxel and 14.1 months when veliparib was added (hazard ratio [HR] = 0.789; P = .231). Median overall survival was 25.9 months and 28.3 months, respectively (HR = .750; P = .157). The overall survival data will be finalized when the prespecified number of events is reached.
Dr. Han and colleagues, however, did not deem this outcome discouraging. “We designed and powered this phase II study to see a dramatic improvement in progression-free survival (a hazard ratio of 0.56). The trial did not meet the primary endpoint in that regard, but we think the trend toward improved progression-free survival and overall survival is encouraging. These results justify the conduct of a larger randomized phase III study,” she said at a press briefing.
She pointed to the “clear difference” in objective response rates as important and noted that these rates were quite high in each arm: 61.3% in the control arm and 77.8% in the veliparib arm (P = .027), although the duration of response was about 11 months in each arm.
In the previous I-SPY 2 phase II study in patients with triple-negative breast cancer, veliparib plus carboplatin increased pathologic complete response rates when added to standard neoadjuvant therapy (51% vs 26%).2 The current study was the first randomized phase II trial to evaluate veliparib plus carboplatin (and paclitaxel) in patients with advanced breast cancer and BRCA1/2 mutations.
Key Study Findings
The phase II study, conducted at 86 sites in 20 countries, enrolled 290 patients with recurrent or metastatic breast cancer, BRCA1 and/or BRCA2 mutations, and no more than 2 previous lines of therapy. Approximately 40% had triple-negative breast cancer. Patients were ineligible if they had been treated with a platinum agent or PARP inhibitor.
Patients were randomized to veliparib at 120 mg twice a day on days 1 to 7 of a 21-day regimen (n = 97) or placebo (n = 99), both with standard carboplatin and paclitaxel; another arm of the trial evaluated veliparib plus temozolomide (n = 94), based on preclinical evidence of synergy. Although Dr. Han did not report these results, she indicated this combination proved inferior to carboplatin plus paclitaxel.
The adverse event profile was similar for carboplatin/paclitaxel and carboplatin/paclitaxel in combination with veliparib. Hematologic toxicity was frequently observed in both arms, consistent with the carboplatin/paclitaxel backbone. More than half of each arm developed grade 3 or 4 neutropenia, and more than one-quarter had grade 3 or 4 thrombocytopenia; grade 3 or 4 febrile neutropenia occurred in 3.1% with placebo and in 8.6% with veliparib arm. Nonhematologic grade 3 or 4 adverse events were infrequent in both arms.
Veliparib is being studied further in combination with weekly paclitaxel and carboplatin in patients with BRCA-mutated advanced breast cancer in the phase III randomized BROCADE3 trial. The study will be powered to detect differences in both progression-free and overall survival of the magnitude observed in this trial. ■
Disclosure: The study was supported by AbbVie. Dr. Han has received institutional research funding from AbbVie, Corcept, Incyte, Karyopharm, Merrimack, Prescient, and TapImmune.
1. Han HS, Dieras V, Robson ME, et al: Efficacy and tolerability of veliparib in combination with carboplatin and paclitaxel vs placebo in patients with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study. 2016 San Antonio Breast Cancer Symposium. Abstract S2-05. Presented December 7, 2016.
This is a good combination, based on an improvement in response rate, but we need phase III data to see if it really works or not.— Virginia Kaklamani, MD
Moderator of the press conference on this study, Virginia Kaklamani, MD, of the University of Texas Health Science...!-->!-->