Abstract OT1-11-01: Phase II study of talazoparib, a PARP inhibitor, in somatic BRCA1/2 mutant metastatic breast cancer identified by cell-free DNA or tumor tissue genotyping
Authors: Vidula Neelima , Damodaran Senthil , Blouch Erica L. , Horick Nora , Ruffle-Deignan Nathan Royce , Bhave Manali , Shah Ami N. , Varella Leticia , Abramson Vandana , Sparano Joseph , Ellisen Leif , Alim Ishraq , Ostrer Harry , Rugo Hope , Bardia Aditya 
Published: March 2023

Abstract
Background: PARP inhibitors are currently approved for the treatment of germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer. We hypothesize that a PARP inhibitor may also have efficacy in somatic BRCA1/2 mutant MBC, expanding the potential clinical applicability of PARP inhibitors. We previously demonstrated that somatic BRCA1/2 mutations can be identified by both cell-free DNA and tumor tissue genotyping in a subset of patients with MBC who are not germline BRCA1/2 carriers. Furthermore, a PARP inhibitor was demonstrated to induce cell growth inhibition in a circulating tumor cell culture model generated from a patient with pathogenic somatic BRCA1 mutant MBC (Vidula, Dubash, CCR, 2020). In this trial, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with somatic BRCA1/2 mutant MBC identified via cell-free DNA or tumor tissue genotyping. Patients are treated with talazoparib, a PARP inhibitor, until disease progression. At baseline and every 3 months, patients undergo CT chest, abdomen, and pelvis, and a bone scan for disease assessment. Patients undergo blood collection at baseline for the Cancer Risk B (CR-B) assay, a novel flow variant assay to assess double-strand break repair mutations in circulating blood cells (Syeda, 2017) and monthly blood collection for cell-free DNA analysis to evaluate changes in the genomic environment. Eligibility Criteria: Patients with MBC with a pathogenic somatic BRCA1/2 mutation identified by cell-free DNA or tumor tissue genotyping are eligible. Both patients with triple-negative breast cancer (≥ 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (≥ 1 prior hormone therapy) are eligible. Patients should not be known germline BRCA1/2 carriers. There is no limit on prior therapies including receipt of a prior platinum (in the absence of disease progression on prior platinum). A prior PARP inhibitor is not allowed. Adequate performance status and organ function are needed. Specific Aims: Primary aim is progression-free survival (PFS) assessed by RECIST 1.1. Secondary aims include objective response rate and toxicity assessed by NCI CTCAE v 5.0. Exploratory aims include assessing impact of BRCA1/2 reversion mutations in cell-free DNA, studying serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to identify changes in the genomic environment, assessing the CR-B assay positivity rate, and correlating these biomarker analyses with patient response. Statistical Methods: This study uses a two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS &gt; 12 weeks) in 53% patients (4% alpha). Accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, and Emory, with pending activation at Northwestern, Cornell, and Vanderbilt. Five patients are enrolled as of 7/2022. Funding: This study is supported by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu
Citation Format: Neelima Vidula, Senthil Damodaran, Erica L. Blouch, Nora Horick, Nathan Royce Ruffle-Deignan, Manali Bhave, Ami N. Shah, Leticia Varella, Vandana Abramson, Joseph Sparano, Leif Ellisen, Ishraq Alim, Harry Ostrer, Hope Rugo, Aditya Bardia. Phase II study of talazoparib, a PARP inhibitor, in somatic BRCA1/2 mutant metastatic breast cancer identified by cell-free DNA or tumor tissue genotyping [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-11-01.