Background: Poly-ADP-ribose polymerase (PARP) represents a family of enzymes of which at least two (PARP1 and PARP2) play important roles in DNA repair. PARP inhibition induces synthetic lethality in tumor cells bearing deleterious mutations in the genes BRCA1/2. Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the PARP enzyme and effectively traps PARP on DNA [1]. In preclinical models, trapping PARP on DNA was more likely to induce cancer cell death than inhibition of PARP alone [1,2]. Talazoparib is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes [1]. Talazoparib has shown promising single-agent anti-tumor efficacy in several solid tumor types and was generally well tolerated in a Phase 1/2 clinical study [3]. Methods: This international Phase 3 trial (EMBRACA) compares the safety and efficacy of talazoparib versus physician’s choice (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with advanced breast cancer. The primary objective is progression free survival (PFS). Secondary objectives include objective response rate (ORR), overall survival (OS), and safety. Exploratory objectives include duration of response (DOR) and health-related quality of life assessments. Subject eligibility includes ≥ 18 years, histologically/cytologically confirmed breast carcinoma, locally advanced and/or metastatic disease, germline BRCA1/2 mutations, ≤ 2 prior chemotherapy-inclusive regimens, prior treatment with a taxane and/or anthracycline, and ECOG performance status ≤ 1. Subjects (n = 429) will be randomized 2:1 to receive either talazoparib oral capsules (1.0 mg/day, 21-day cycles) or physician’s choice treatment. This trial is currently enrolling patients from the United States, Asia/Pacific, Europe, Israel, and South America (NCT01945775). [1] Murai J et al. Mol Cancer Ther. 2014;13:433-443. [2] Murai J et al. Cancer Res. 2012;72(21):5588-5599. [3] Wainberg ZA et al. J Clin Oncol. 2014;32(suppl):5; abstr 7522 Clinical trial information: NCT01945775