Phase II study of a PARP inhibitor in somatic BRCA1/2 mutant metastatic breast cancer (MBC).

TPS1134 Background: While PARP inhibitors are approved for germline BRCA1/2 mutant MBC, and are shown to improve both patient quality of life and progression-free survival (PFS), as a well-tolerated oral targeted therapy, their utility is limited as germline BRCA1/2 mutations are present in 5-10% of breast cancer. We hypothesize that somatic BRCA1/2 mutations may also respond to PARP inhibitors. We have demonstrated that somatic BRCA1/2 mutations can be identified by cell-free DNA and tumor tissue genotyping assays in patients who are not known germline BRCA1/2 carriers, and some of these are pathogenic. Using a circulating tumor cell culture model developed from a patient with a pathogenic somatic BRCA1 mutation, we have shown that a PARP inhibitor can induce cell growth inhibition paralleling germline BRCA1/2 mutant lines. In this trial, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may help expand the number of patients with MBC who benefit from a PARP inhibitor. Methods: In this phase II investigator-initiated clinical trial, 30 patients with MBC harboring somatic BRCA1/2 mutations identified via a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are evaluated for pathogenicity using validated genomic databases such as ClinVar by genetic counselors prior to enrollment. Patients may have metastatic triple-negative or hormone receptor positive (HR+)/HER2- breast cancer progressing on 1 prior therapy, and should not be known germline BRCA1/2 carriers. Any number of prior therapies are allowed but patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day (a PARP inhibitor with high potency) until disease progression. Imaging (CT chest abdomen and pelvis as well as bone scan) occurs at baseline and every 3 months for disease assessment. The primary endpoint is progression-free survival (RECIST 1.1). This study has 81% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Key secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Correlative studies include collecting cell-free DNA at baseline and monthly to identify the emergence of resistance mutations and impact of BRCA1/2 reversion mutations and mutant allele fraction on response, and evaluating the Cancer Risk B (CR-B) assay, a novel method that identifies double-strand break repair mutations in circulating blood cells. The study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, Emory, University of California San Francisco, and Northwestern, and pending activation at Vanderbilt and Cornell, with 11 patients enrolled as of 2/2023. Clinical trial information: NCT03990896 .