As reported in The Lancet Oncology by Véronique Diéras, MD, of the Institut Curie, Paris, and Centre Eugène Marquis, Rennes, and colleagues, the phase III BROCADE3 trial has shown a significant improvement in progression-free survival with the addition of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to carboplatin/paclitaxel in patients with previously treated germline BRCA-mutated HER2-negative advanced breast cancer.¹

Study Details

In the ongoing double-blind trial, 509 patients (intent-to-treat population) from sites in 36 countries who had received up to two previous lines of chemotherapy for metastatic disease were randomly assigned 2:1 between July 2014 and January 2018 to receive carboplatin at AUC 6 on day 1 and paclitaxel at 80 mg/m² on days 1, 8, and 15 of 21-day cycles, combined with either veliparib at 120 mg twice daily on days −2 to 5 (n = 337) or matching placebo (n = 172).

Véronique Diéras, MD

Patients discontinuing carboplatin and paclitaxel before disease progression could continue veliparib (or placebo) at an intensified dose of 300 mg twice daily continuously, increased to 400 mg twice daily, if tolerated, until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. The primary endpoint was investigator-assessed progression-free survival.

Progression-Free Survival

Median follow-up at data cutoff (April 2019) was 35.7 months in the veliparib group and 35.5 months in the control group. A total of 41% of the veliparib group and 34% of the control group discontinued carboplatin and paclitaxel before disease progression and received blinded study drug monotherapy.

Median progression-free survival was 14.5 months (95% confidence interval [CI] = 12.5–17.7 months) in the veliparib group vs 12.6 months (95% CI = 10.6–14.4 months) in the control group (hazard ratio [HR] = 0.71, 95% CI = 0.57–0.88; P = .0016). Progression-free survival rates at 2 and 3 years were 33.6% vs 19.8% and 25.7% vs 10.7%. In a sensitivity analysis of progression-free survival on blinded independent central review, median progression-free survival was 19.3 months (95% CI = 16.5–23.3 months) vs 13.5 months (95% CI = 12.5–16.3 months), with a hazard ratio of 0.70 (95% CI = 0.54–0.90; P = .0054).

An objective response was observed in 75.8% vs 74.1% of patients, with a median duration of response of 14.7 vs 11.0 months. Clinical benefit (defined as progression-free survival at week 24) was observed in 90.7% vs 93.2% of patients. Median progression-free survival 2 (the time from randomization to second disease progression) was 21.3 months vs 17.4 months (HR = 0.76, 95% CI = 0.60–0.96).

In an interim analysis of overall survival at data cutoff, median overall survival was 33.5 months (95% CI = 27.6–37.9 months) in the veliparib group and 28.2 months (95% CI = 24.7–35.2 months) in the control group (HR = 0.95, 95% CI = 0.73–1.23, P = .67). Overall survival rates at 2 and 3 years were 61.3% vs 59.8% and 46.4% vs 39.3%. At the time of analysis, 44% of the control group had crossed over to open-label veliparib as their first subsequent anticancer therapy. Any subsequent anticancer therapy was received by 54.0% vs 71.5% of patients.

Adverse Events

Grade ≥ 3 adverse events occurred in 97% of the veliparib group vs 96% of the control group, the most common being neutropenia (81% vs 84%), anemia (42% vs 40%), and thrombocytopenia (40% vs 28%). Serious adverse events occurred in 34% vs 29% of patients (including disease progression in 4% of each group), the most common (excluding disease progression) being anemia (4.8%) and thrombocytopenia (4.2%) in the veliparib group and anemia (2.9%) in the control group. Adverse events (excluding disease progression) led to discontinuation of veliparib in 10% of patients and placebo in 0% of patients, carboplatin in 47% vs 37%, and paclitaxel in 43% vs 43%. Secondary malignancies occurred in six vs three patients (both 1.8%).

Deaths due to adverse events occurred in six patients (2%) in the veliparib group (four due to malignant neoplasm progression, one to pulmonary embolism, and one to sepsis) and in three patients (2%) in the control group (two due to malignant neoplasm progression and one to pulmonary artery thrombosis). None of the deaths was considered related to treatment.

During blinded monotherapy, the most common grade ≥ 3 adverse event in patients receiving veliparib was nausea (5% vs 2% in those receiving placebo). The most common serious adverse event was seizure (2% vs 0%).

The investigators concluded: “The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation–associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.” 

DISCLOSURE: The study was funded by AbbVie. Dr. Diéras has served as a consultant or advisor to Roche-Genentech, Novartis, Lilly, Pfizer, AbbVie, Merck Sharpe & Dohme, Daiichi Sankyo, Seattle Genetics, and AstraZeneca and has received speakers fees from Roche-Genentech, Novartis, Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo.

REFERENCE

1. Diéras V, Han HS, Kaufman B, et al: Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. August 27, 2020 (early release online).