Abstract OT1-03-16: EMBRACA: A phase 3, open-label, randomized, parallel, 2-arm international study of the oral PARP inhibitor talazoparib (BMN 673) versus physician's choice in BRCA mutation subjects with locally advanced and/or metastatic breast cancer
Authors: Litton JK , Blum JL , Im Y-H , Martin M , Mina L , Roché H , Visco F , Yang X , Lokker NA , Lounsbury DL , Eiermann W 
Published: May 2016

Abstract
Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, which is initiated by poly-(ADP-ribose) polymerase (PARP) [1-3]. In cells with deleterious BRCA1/2 mutations, PARP inhibition is synthetically lethal because of accumulation of irreparable DNA damage [1-3]. Talazoparib (BMN 673) exhibits a novel two-pronged approach in treating BRCA1/2-mutant tumors: 1) potent catalytic inhibition of the PARP enzyme; and 2) trapping of PARP at sites of DNA damage [4-7]. The capacity to trap PARP-DNA complexes varies widely across PARP inhibitors and is not correlated with catalytic inhibition potency [4-7]. In preclinical models, trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone [4,7]. Talazoparib is the most potent clinical-stage PARP inhibitor tested to date with the highest efficacy at trapping PARP-DNA complexes [7]. Talazoparib has shown single-agent antitumor efficacy in several solid tumor types and was generally well tolerated in a phase 1/2 clinical study [8].
Methods: This open-label, randomized, parallel, 2-arm, phase 3 international trial (EMBRACA) compares the safety and efficacy of talazoparib with 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) for objective responders and health-related quality of life measurements. Subject eligibility includes age ≥18 years with histologically/cytologically confirmed breast carcinoma, locally advanced and/or metastatic disease, germline BRCA1/2 mutations, ≤2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline, and Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Subjects (n=429) will be randomized 2:1 to receive either talazoparib oral capsules (1 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).
This study is funded by BioMarin Pharmaceutical Inc.
References:
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Citation Format: Litton JK, Blum JL, Im Y-H, Martin M, Mina L, Roché H, Visco F, Yang X, Lokker NA, Lounsbury DL, Eiermann W. EMBRACA: A phase 3, open-label, randomized, parallel, 2-arm international study of the oral PARP inhibitor talazoparib (BMN 673) versus physician's choice in BRCA mutation subjects with locally advanced and/or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-16.