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Talazoparib Improves Progression-Free Survival in Advanced Breast Cancer With Germline BRCA Mutation


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Jennifer K. Litton, MD

Jennifer K. Litton, MD

As reported in The New England Journal of Medicine by Jennifer K. Litton, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, the phase III EMBRACA trial has shown significantly improved progression-free survival with the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib vs physician’s choice of standard single-agent therapy in patients with advanced breast cancer and germline BRCA1/2 mutation.1

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’s 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.

Talazoparib in Advanced Breast Cancer

  • Talazoparib significantly improved progression-free survival vs standard single-agent therapy.
  • Improvements were seen in all major subgroups.

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 (CNS) metastases. The primary endpoint was progression-free survival in the intention-to-treat population assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors v1.1.

For the talazoparib vs standard-therapy groups, the median age was 45 vs 50 years (63% vs 47% < 50 years); 98% vs 99% had an Eastern Cooperative Oncology Group performance status of 0 or 1; 94% in both groups had metastatic disease; 76% vs 79% had measurable disease; 45% vs 42% had triple-negative disease and 55% vs 58% had hormone receptor–positive disease; 46% vs 44% were BRCA1-positive and 54% vs 56% were BRCA2-positive; 83% vs 84% had previous neoadjuvant or adjuvant therapy; the median number of prior hormone therapy regimens in hormone receptor–positive patients was two in both groups; 16% vs 21% had prior platinum therapy; and 39% vs 38% had received no prior cytotoxic regimen for advanced disease, with 61% vs 62% receiving 1 to 3 prior regimens.

Progression-Free Survival

The median duration of follow-up for progression-free survival was 11.2 months. The 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 CNS metastases (0.32, 95% CI = 0.15–0.68, for yes; 0.58, 95% CI = 0.43–0.78, for no), and BRCA1 (0.59, 95% CI = 0.39–0.90) or BRCA2 mutation (0.47, 95% CI = 0.32–0.70).

At interim analysis for overall survival (at 57% of projected events), the 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 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.

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.
— Jennifer K. Litton, MD

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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.” ■

DISCLOSURE: The study was funded by Medivation (Pfizer). Dr. Litton is a consultant/advisor for Pfizer, AstraZeneca, Medivation/Pfizer; is on the speakers bureau of Medscape, Physician Education Resource, Med Learning Group, UpToDate; has received institutional research funding from GlaxoSmithKline, Medivation/Pfizer, Novartis, Bristol-Myers Squibb, Genentech, Pfizer, EMD Serono, Jounce Therapeutics, and UpToDate; has patents, royalties, and other intellectual property from UpToDate; and has received travel expenses from Physician Education Resource, Med Learning Group, Medscape, and UpToDate. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Litton JK, Rugo HS, Ettl J, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018.


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