P1.01A phase 3 study of the oral PARP inhibitor talazoparib (BMN 673) in BRCA mutation subjects with advanced breast cancer (EMBRACA).

BACKGROUND: Poly-ADP-ribose polymerase (PARP) enzymes are important in DNA repair. PARP inhibition induces lethality in tumor cells with mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2). Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that both potently inhibits the PARP enzyme and effectively traps PARP on DNA, resulting in cell death in BRCA1/2-mutated cells.[1, 2] Talazoparib has shown promising single-agent antitumor efficacy in several solid tumor types and generally well tolerated in an ongoing Phase 1/2 clinical study[3].

METHODS: This multi-center, global, Phase 3 trial (EMBRACA) compares the safety and efficacy of talazoparib versus physician's choice treatment (capecitabine, eribulin, gemcitabine or vinorelbine) in locally advanced and/or metastatic breast cancer subjects with germline BRCA mutations. The primary study objective is to evaluate progression-free survival (PFS) in subjects treated with talazoparib as a monotherapy compared with those treated with protocol-specific physician's choice. Secondary objectives include objective response rate (ORR), overall survival (OS), and safety. Patients may be eligible if they are ≥18 years, have histologically/cytologically confirmed breast carcinoma, locally advanced and/or metastatic disease, documentation of a deleterious or pathogenic germline BRCA1 or BRCA2 mutation, ≤2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline in the adjuvant or metastatic setting, ECOG performance status ≤1, and no prior platinum treatment for metastatic disease. Patients (n = 429) will be randomized 2:1 to receive either talazoparib oral capsules (1.0mg/day, 21-day cycles) or physician's choice treatment. All eligible subjects will receive study drug treatment until disease progression or unacceptable toxicity. This trial is enrolling patients from Europe, Asia/Pacific, Israel, South America, and the United States (NCT01945775).