The addition of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to carboplatin/paclitaxel chemotherapy significantly improved progression-free survival in patients with advanced HER2-negative breast cancer and germline BRCA mutation compared with placebo plus chemotherapy, according to the results of the double-blind, phase III BROCADE3 study. These findings were presented at the 2019 European Society for Medical Oncology (ESMO) Congress.1
The median progression-free survival for both arms was more than 12 months, but it was 1.9 months higher with veliparib than with the control. Notably, a more durable benefit for progression-free survival was observed with veliparib: 26% of patients treated with veliparib remained alive and progression-free at 3 years, compared with 11% of patients receiving placebo/chemotherapy.
Véronique Diéras, MD
“The addition of veliparib to carboplatin/paclitaxel provided a statistically significant and clinically meaningful benefit in patients with HER2-negative advanced breast cancer and BRCA mutation. The hazard ratio for disease progression was reduced by 29%,” said lead author Véronique Diéras, MD, of the Institut Curie, Paris, and Centre Eugène Marquis, Rennes. “This is the first phase III trial to evaluate a PARP inhibitor combined with a highly active platinum therapy, and patients with HER2-negative advanced breast cancer and a germline BRCA mutation should be offered this option,” Dr. Diéras stated.
The rationale for the PARP/platinum combination is that BRCA-mutated tumors are deficient in homologous recombination repair genes, making them susceptible to both platinum and PARP1/2 inhibitors such as veliparib. “Earlier studies of this combination have been challenging due to exaggeration of myelosuppression. Veliparib inhibits PARP with minimal ‘PARP trapping,’ which theoretically may allow for improved tolerability when combined with platinum,” Dr. Diéras explained.
A total of 509 patients were randomly assigned 2:1 to receive oral veliparib at 120 mg twice daily or placebo on days 2 to 5, administered with carboplatin AUC 6 on day 1 and weekly paclitaxel at 80 mg/m2 on days 1, 8, and 15 in 21-day cycles. Patients discontinuing both carboplatin and paclitaxel without disease progression received blinded single-agent veliparib at 300 to 400 mg twice daily or placebo. Treatment was continued until disease progression or unacceptable toxicity. Crossover to veliparib was allowed at disease progression.
Baseline characteristics were comparable between the two study arms. All patients had germline BRCA1/2 mutations and had been previously treated with up to two prior lines of cytotoxic therapy for metastatic breast cancer; 8% of patients received prior platinum therapy and 19% received chemotherapy for metastatic disease. The median age of study patients was 47 years (range, 24–82 years); 48% of patients had hormone receptor–negative disease (ie, they had triple-negative breast cancer); and 4% had a history of central nervous system metastases.
The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival, clinical benefit rate, objective response rate, and progression-free survival 2 (time from randomization to disease progression or death).
The median progression-free survival per investigator assessment was 14.5 months in 337 patients treated with veliparib plus chemotherapy, compared with 12.6 months in 172 patients who received placebo plus chemotherapy (P = .002). The median progression-free survival per independent review committee was longer at 19.3 months, compared with 13.5 months, respectively. At 3 years, progression-free survival was twice as long with veliparib plus chemotherapy vs chemotherapy (26% vs 11%). A progression-free survival benefit was observed for veliparib in all subgroups studied, with the exception of a small group of patients with brain metastases.
“This is the first phase III trial to evaluate a PARP inhibitor combined with a highly active platinum therapy, and patients with HER2-negative advanced breast cancer and a germline BRCA mutation should be offered this option.”— Véronique Diéras, MD
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At interim analysis, the median overall survival was 33.5 months with veliparib/chemotherapy, compared with 28.2 months with placebo/chemotherapy (P = .67). A total of 44% of patients in the chemotherapy arm crossed over to veliparib.
The clinical benefit (complete response plus partial response plus stable disease) and the objective response rates were similar between the study arms. At 24 weeks, the clinical benefit rate was 90.7% with veliparib and 93.2% with placebo; the objective response rate was 75.8% vs 74.1%, respectively.
Progression-free survival 2 was prolonged with veliparib: 21.3 months vs 17.4 months with chemotherapy alone. The median duration of response was 14.7 months vs 11.0 months, respectively.
The addition of veliparib did not alter the safety profile of chemotherapy substantially. Most patients in each treatment arm experienced an adverse event of special interest; adverse events of any grade included neutropenia in 91% of patients on both arms; thrombocytopenia in 82% of the veliparib arm vs 72% in the chemotherapy/placebo arm; anemia in 81% vs 70%, respectively; and nausea and vomiting in 75% vs 68%, respectively.
The most common treatment-related grade 3 and higher adverse events occurring in at least 20% of patients in the respective arms were anemia (27% vs 17%), neutropenia (52% vs 50%), and thrombocytopenia (25% vs 15%).
Dose reductions in carboplatin were needed for 88% of patients treated with veliparib/chemotherapy, compared with 86% of patients who received placebo with chemotherapy, and 74% vs 70%, respectively, required a dose reduction in paclitaxel.
DISCLOSURE: The BROCADE3 study was funded by AbbVie. Dr. Diéras reported financial relationships with Roche/Genentech, Novartis, Lilly, Pfizer, Eisai, Nektar, Astellas, AbbVie, Merck Sharp & Dohme, Tesaro, Daiichi Sankyo, Odonate, Seattle Genetics, and AstraZeneca.
1. Diéras VC, Han HS, Kaufman B, et al: Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer. 2019 ESMO Congress. Abstract LBA9. Presented September 29, 2019.
Sherene Loi, MD, of Peter MacCallum Cancer Centre, Melbourne, Australia, said that the BROCADE3 trial was positive because it met its primary endpoint. However, she expressed some reservations about adopting this combination as a new standard for HER2-negative BRCA-mutated advanced breast cancer.