Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that inhibits the PARP enzyme and effectively traps PARP on single-stranded DNA breaks, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent physician's choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). The primary objective was PFS assessed by blinded independent central review (BICR). Secondary objectives: OS, ORR, CBR at 24 weeks (CBR24), and safety. Exploratory objectives: patient-reported QoL and DOR. Eligibility criteria: age ≥ 18 years; HER2-negative aBC; deleterious or suspected deleterious gBRCAmut; ≤ 3 prior cytotoxic regimens for aBC; and ECOG PS ≤ 2. Prior platinum was allowed. Patients were randomized 2:1 and stratified by receptor status, extent of prior therapy, and CNS metastases (NCT01945775). Results: 431 patients were randomized (median age 46 years; 54% hormone-receptor [HR]+ BC; 45% BRCA1+ and 55% BRCA2+; 55% ECOG PS = 0; 38% chemo-naïve for aBC; 18% prior platinum; 15% CNS metastases); 287 were assigned to TALA and 144 to PCT (1 TALA, 18 PCT patients were not treated). Median duration of exposure was 6.1 and 3.9 months, respectively; TALA had a relative dose intensity of 87%. At 62% PFS data maturity: TALAPCTHazard Ratio/Odds Ratio (P value)PFS by BICR, mo (95% CI)8.6 (7.2-9.3); n = 2875.6 (4.2-6.7); n = 1440.542 (< 0.0001)OS [interim], mo (95% CI)22.3 (18.1-26.2); n = 28719.5 (16.3-22.4); n = 1440.761 (0.105)ORR by INV, % (95% CI)62.6% (55.8-69.0); n = 21927.2% (19.3-36.3); n = 1144.99 (< 0.0001)DOR by INV, mo (IQR)5.4 (2.8-11.2); n = 1373.1 (2.4-6.7); n = 310.431 (0.0005)*CBR24 by INV, % (95% CI)68.6% (62.9-74.0); n = 28736.1% (28.3-44.5); n = 1444.28 (≤0.0001) INV, investigator. *Not a randomized subset. Improved clinical benefit was seen in all subsets including those with HR+ BC (HR 0.47; 95% CI 0.32-0.71) and CNS metastasis (HR 0.32; 95% CI 0.15-0.88). There was a significant delay in the time to deterioration in global health status (GHS)/QoL for TALA vs PCT (HR 0.38; 95% CI 0.26-0.55; P < 0.0001]. Grade 3-4 hematologic adverse events (AEs) occurred in 55% TALA (mainly anemia)/39% PCT (mainly neutropenia). Grade 3-4 non-hematologic AEs were seen in 32% TALA/38% PCT; TALA was associated with fewer gastrointestinal disorders (5.6% vs 11.9%) and skin/subcutaneous tissue disorders (0.7% vs 5.6%) than PCT. Grade 3-4 serious AEs were observed in 26% TALA/25% PCT. AEs associated with permanent study drug discontinuation occurred in 8% TALA/10% PCT. AE resulting in death occurred in 2.1% TALA/3.2% PCT.Conclusions: Single-agent TALA significantly prolonged PFS by BICR in HER2-negative aBC patients with a gBRCAmut compared to PCT; all key secondary efficacy endpoints demonstrated benefit with TALA, with a significant delay in time to deterioration in GHS/QoL. TALA was generally well tolerated with minimal non-hematologic toxicity and few AEs associated with treatment discontinuations. Citation Format: Litton J, Rugo HS, Ettl J, Hurvitz S, Gonçalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im Y-H, Quek RGW, Tudor IC, Hannah AL, Eiermann W, Blum JL. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-07.