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

Véronique Diéras, MD

Study Details

The ongoing double-blind trial included 509 patients (intent-to-treat population) from sites in 36 countries who had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned 2:1 between July 2014 and January 2018 to receive to 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).

Patients discontinuing carboplatin and paclitaxel before disease progression could continue veliparib (or placebo) at an intensified dose of 300 mg twice daily continuously—escalated 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 for patients in the veliparib group and 35.5 months in the control group. A total of 41% of patients in the veliparib group and 34% of patients in 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 at 2 and 3 years was 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).

Objective response was observed in 75.8% vs 74.1% of patients, with median durations 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.

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). At the time of analysis, 44% of patients in the control group had crossed over to open-label veliparib.

Adverse Events

Grade ≥ 3 adverse events occurred in 97% of the veliparib group vs 96% of the control group, with 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. Adverse events led to discontinuation of veliparib in 16% of patients and placebo in 11% of patients, carboplatin in 50% vs 41%, and paclitaxel in 46% vs 46%.

Deaths due to adverse events occurred in six patients (2%) in the veliparib group (4 due to malignant neoplasm progression, 1 to pulmonary embolism, and 1 to sepsis) and in three patients (2%) in the control group (2 due to malignant neoplasm progression and 1 due to pulmonary artery thrombosis). None of the deaths was considered related to treatment.

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.”

Dr. Diéras, of the Institut Curie, Paris, and Centre Eugène Marquis, Rennes, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AbbVie. For full disclosures of the study authors, visit thelancet.com.