Abstract OT2-01-13: A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germlineBRCAmutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA)

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, regulated by poly(ADP-ribose) polymerase (PARP). Inhibition of PARP results in synthetic lethality in cells with a BRCA1/2 mutation because of accumulation of irreparable DNA damage; PARP inhibitors have the potential to be selectively toxic for BRCA-mutated cells. In addition to catalytic inhibition, it has been shown that some PARP inhibitors induce PARP trapping at sites of DNA damage. The capacity to trap PARP-DNA complexes varies widely across different PARP inhibitors and is not correlated with PARP catalytic inhibition. Preclinical models have shown trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone. Talazoparib is a dual-mechanism PARP inhibitor that both inhibits the PARP enzyme and effectively traps PARP on DNA, preventing DNA damage repair and resulting in cell death in BRCA1/2-mutated cells. In preclinical studies, talazoparib at nanomolar concentrations showed the highest efficiency at trapping PARP-DNA complexes relative to other PARP inhibitors. In a previous phase 1/2 clinical study, talazoparib as monotherapy (1 mg once daily) resulted in a 50% response rate and an 86% clinical benefit rate at 24 weeks in 14 patients with a germline BRCA1/2 mutation and advanced breast cancer (aBC). Methods: This open-label, randomized, 2-arm, international phase 3 trial (EMBRACA) compares the efficacy and safety of talazoparib with protocol-specific physician9s choice (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with aBC. The primary objective is progression-free survival by central imaging. Secondary objectives are objective response rate, overall survival, safety and pharmacokinetics of talazoparib. Exploratory objectives include health-related quality of life measurements and biomarker research in blood and tumor samples that may permit characterization of mechanisms involved in tumor sensitivity and resistance to talazoparib. Key patient eligibility criteria include aged ≥18 years with histologically/cytologically confirmed breast cancer; locally advanced and/or metastatic disease appropriate for systemic single-agent cytotoxic chemotherapy; deleterious or pathogenic germline BRCA1/2 mutations by central laboratory; ≤3 prior cytotoxic chemotherapy regimens for advanced disease (prior platinum is allowed provided patients did not relapse within 6 months in the adjuvant setting or did not progress on platinum therapy); prior treatment with a taxane and/or anthracycline unless medically contraindicated; and ECOG performance status ≤2. Patients (N=429) will be randomized 2:1 to receive either talazoparib capsules (1 mg/day, 21-day cycles) or physician9s choice treatment. This trial is currently enrolling patients from the USA, Europe, Israel, Ukraine, Russia, Korea, Australia, Taiwan and Brazil (NCT01945775). This study is funded by Medivation, Inc. Citation Format: Litton J, Ettl J, Hurvitz SA, Mina LA, Rugo HS, Lee K-H, Yerushalmi R, Woodward N, Goncalves A, Moreno F, Roche H, Im Y-H, Martin M, Bhattacharya S, Peterson A, Hannah A, Eiermann W, Blum J. A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-13.