EMBRACA Trial Compares Talazoparib vs Standard Therapy in Advanced Breast Cancer With a Germline BRCA Mutation
As reported in The New England Journal of Medicine by Litton et al, the phase III EMBRACA trial has shown significantly improved progression-free survival with the poly (ADP-ribose) polymerase inhibitor talazoparib vs physician choice of standard single-agent therapy in patients with advanced breast cancer and a germline BRCA1 or BRCA2 mutation.
Study Details
In the open-label trial, 431 patients from 145 sites in 16 countries were randomized 2:1 between October 2013 and April 2017 to receive oral talazoparib at 1 mg once daily (n = 287) or physician choice of standard single-agent therapy (n = 144) with capecitabine (44%), eribulin (Halaven; 40%), gemcitabine (10%), or vinorelbine (7%) in continuous 21-day cycles. Patients had locally advanced breast cancer not amenable to curative therapy or metastatic disease. They had received no more than three previous cytotoxic regimens for advanced breast cancer and had received previous treatment with a taxane or an anthracycline or both (unless contraindicated).
Prior neoadjuvant or adjuvant platinum-based therapy was permitted if the patient had a disease-free interval of at least 6 months after the last dose. There was no limit on the number of previous hormone therapies received by patients with hormone receptor–positive disease. Patients with HER2-positive disease were not eligible. Randomization was stratified by the number of previous cytotoxic chemotherapy regimens for advanced disease (0 vs 1–3), hormone receptor status (triple-negative vs hormone receptor–positive), and history of central nervous system metastases.
The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.
Survival and Response Data
Median duration of follow-up for progression-free survival was 11.2 months. Median progression-free survival was 8.6 months in the talazoparib group vs 5.6 months in the standard therapy group (hazard ratio [HR] = 0.54, P < .001). Progression-free survival at 1 year was 37% vs 20%. Hazard ratios favored talazoparib in all subgroups analyzed, including the number of previous cytotoxic regimens (0.57, 95% confidence interval [CI] = 0.34–0.95, for 0; 0.51, 95% CI = 0.33–0.80 for 1; 0.56, 95% CI = 0.34–0.95 for ≥ 2), triple-negative disease (0.60, 95% CI = 0.41–0.87), hormone receptor–positive disease (0.47, 95% CI = 0.32–0.71), history of central nervous system metastases (0.32, 95% CI = 0.15–0.68, for yes; 0.58, 95% CI = 0.43–0.78, for no), and mutation in BRCA1 (0.59, 95% CI = 0.39–0.90) or BRCA2 (0.47, 95% CI = 0.32–0.70).
At interim analysis for overall survival (at 57% of projected events), median overall survival was 22.3 vs 19.5 months (HR = 0.76, P = .11). Cancer therapy was received by 62% vs 68% of patients after study treatment. The objective response rate was 62.6% vs. 27.2% (odds ratio = 5.0, P < .001).
Adverse Events
Grade 3 or 4 hematologic adverse events occurred in 55% of the talazoparib group vs 38% of the standard therapy group, with the most common such events in the talazoparib group being anemia (39% vs 5%) and neutropenia (21% vs 35%). Nonhematologic grade 3 adverse events (no grade 4 events reported) occurred in 32% vs 38%, with the most common in the talazoparib group being vomiting, back pain, and dyspnea (2.4% each).
Serious adverse events occurred in 32% vs 29% of patients. Adverse events led to treatment discontinuation in 5.9% vs 8.7% of patients and to dose modification in 66% vs 60%. The most common causes of dose modification were anemia, neutropenia, and thrombocytopenia in the talazoparib group and neutropenia, palmar–plantar erythrodysesthesia, nausea, and diarrhea in the standard therapy group.
Assessment by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) indicated an improvement in global health status with talazoparib vs deterioration with standard therapy (P < .001) and significant delays to clinically meaningful deterioration on both the QLQ-C30 (HR = 0.38, 95% CI = 0.26–0.56) and the EORTC QLQ-BR23 scale for breast symptoms (HR = 0.39, 95% CI = 0.20–0.78).
The investigators concluded, “Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib.”
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