Abstract OT1-1-14: A phase 2, 2-stage, 2-cohort study of the oral PARP inhibitor BMN 673 in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO 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 BRCA1 and BRCA2, both of which are key components in the homologous recombination DNA double-strand breaks repair pathway. 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 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 Phase 2 trial (ABRAZO) is to evaluate the safety and efficacy of BMN 673 in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. This study is an open-label, 2-stage, 2-cohort Phase 2 study using a Southwest Oncology Group (SWOG) 2-stage design. Eligible subjects will be assigned to either Cohort 1 (n=70) or 2 (n=70) based on prior chemotherapy exposure for metastatic disease: Cohort 1) Subjects who have previously responded to a platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum; or Cohort 2) Subjects who have received > 2 prior chemotherapy regimens and who have had no prior platinum therapy for metastatic disease. The primary objective is to determine the objective response rate (ORR) of BMN 673 as a single agent for each cohort. The secondary objectives of the study are to determine the following for each cohort: clinical benefit rate (CBR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). Health-related quality of life assessment is an exploratory objective. 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, deleterious or pathogenic germline BRCA1 or BRCA2 mutation, prior chemotherapy for metastatic disease based on the above Cohort 1 or Cohort 2 inclusion criteria, ECOG performance status ≤ 1, and no central nervous system (CNS) metastasis except adequately treated brain metastasis documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids for management of CNS symptoms. Eligible patients will receive BMN 673 oral capsules once daily (1.0 mg/day) continuously in 21-day cycles until disease progression or unacceptable toxicity. This trial is enrolling patients from the United States and European countries (NCT02034916). Citation Format: Nicholas C Turner, Judith Balmana, Susan M Domchek, Frances Visco, Charlie Zhang, Nathalie A Lokker, Debra L Lounsbury, Mark E Robson. A phase 2, 2-stage, 2-cohort study of the oral PARP inhibitor BMN 673 in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO 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 OT1-1-14.