A Phase 3, Open-Label, Randomized, Parallel, 2-Arm Multi-Center Study Of The Oral Parp Inhibitor Bmn 673 Versus Physician'S Choice In Germline Brca Mutation Subjects With Locally Advanced And/Or Metastatic Breast Cancer (Embraca Study)

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 mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA 1) and breast cancer susceptibility gene 2 (BRCA 2), both of which are key components in the pathway of homologous recombination DNA repair. BMN 673 is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes (Murai et al, 2014). BMN 673 is a novel and highly potent PARP inhibitor and has shown promising single-agent anti-tumor efficacy in several tumor types in an ongoing Phase 1/2 clinical study. Methods: The purpose of this multi-center, international, open-label, 2:1 randomized Phase 3 trial (EMBRACA) is to compare the safety and efficacy of BMN 673 versus protocol-specific physician’s choice treatment (capecitabine, eribulin, gemcitabine or vinorelbine) in subjects who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. The primary objective of the study is to compare progression free survival (PFS) of subjects treated with BMN 673 as a monotherapy relative to those treated with protocol-specific physician’s choice treatment. Secondary objectives include objective response rate (ORR), overall survival (OS), safety and pharmacokinetics of BMN 673. Exploratory objectives include duration of response (DOR) and health-related quality of life assessment. Patients may be eligible if they are 18 years or older, have histologically or cytologically confirmed carcinoma of the breast, locally advanced and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy, 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 BMN 673 oral capsules once daily (1.0 mg/day) in 21-day cycles or protocol-specific physician’s choice treatment. All eligible subjects will receive study drug treatment until disease progression or unacceptable toxicity. This trial is enrolling patients from the United States, Europe, Israel, Asia/Pacific, and South America (NCT01945775). Citation Format: Jennifer K Litton, Joanne L Blum, Wolfgang Eiermann, Young-Hyuck Im, Miguel Martin, Lida Mina, Henri Roche, Hope S Rugo, Frances Visco, Charlie Zhang, Nathalie A Lokker, Debra L Lounsbury. A phase 3, open-label, randomized, parallel, 2-arm multi-center study of the oral PARP inhibitor BMN 673 versus physician9s choice in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-12.