Abstract OT2-03-03: Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: Genotyping based clinical trial
Authors: Vidula Neelima , Horick Nora , Basile Erin , Sutherland Sara , Fax Ruth , Haber Daniel , Ellisen Leif , Rugo Hope S. , Bardia Aditya 
Published: March 2020

Background: Metastatic breast cancer (MBC) accounts for most breast cancer deaths. In 2018, two Poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib and talazoparib, were approved for the treatment of MBC patients with germline BRCA1 or 2 mutations based on the OlympiAD and EMBRACA trials (Robson, NEJM, 2017 and Litton, NEJM, 2018), which demonstrated improvement in progression-free survival (PFS) with PARP inhibitors compared to chemotherapy. These landmark findings have triggered much interest in studying PARP inhibitors in MBC, but germline BRCA mutations only account for 5-10% of breast cancer patients. A critical question is whether PARP inhibitors may also be beneficial in MBC with somatic BRCA1 or 2 mutations, similar to somatic BRCA mutant ovarian cancer where they are effective(George, Oncotarget, 2017). Liquid biopsies via circulating cell-free DNA (cfDNA) may unveil somatic mutations. We previously demonstrated (Vidula, SABCS, PD1-13, 2017) that a subset of MBC patients have detectable somatic cfDNA BRCA1 or 2 mutations, in the absence of germline BRCA mutations, highlighting the role of liquid biopsies for detection of somatic BRCA mutations in MBC. Based on our preliminary data, we hypothesize that we can utilize liquid biopsies to detect somatic BRCA1 or 2 mutations and guide therapy selection with a PARP inhibitor in patients with MBC.

Methods: In this single arm phase II clinical trial we will evaluate the efficacy and safety of a PARP inhibitor, talazoparib, in patients with somatic BRCA mutant MBC (N=30). Patients will undergo cfDNA screening to identify cfDNA somatic BRCA1 or 2 deleterious mutations. Patients without known BRCA germline mutations who have cfDNA BRCA1 or 2 mutations will be enrolled at the Massachusetts General Hospital and University of California San Francisco. The study will enroll both patients with hormone receptor positive/HER2 negative breast cancer and triple-negative breast cancer whose disease has progressed on at least 1 prior line of endocrine therapy and at least 1 prior line of chemotherapy for MBC, respectively. Patients may have received any number of prior lines of therapy.

Eligible patients will be treated with talazoparib 1 mg daily until progression (evaluated with serial CT chest/abdomen/pelvis and bone scan) or unacceptable toxicity. The primary endpoint is to determine PFS by RECIST 1.1. Patients will be enrolled in a two-stage design, providing 80% power to demonstrate that the treatment is associated with “success” (PFS &gt; 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety/tolerability (NCI CTCAE v5.0). Serial cfDNA will be collected at baseline and during treatment to evaluate for changes in the BRCA cfDNA mutant allelic fraction in response to therapy. The impact of pre-existing resistance mutations in baseline cfDNA, particularly BRCA reversion mutations that can occur with prior platinum exposure (Weigelt, CCR, 2017), on outcomes will be studied. Paired liquid biopsies (pre- and post-treatment) will be compared to generate hypotheses about potential novel targets for future combination studies with talazoparib to improve response(exploratory objective). This study may help expand the applicability of talazoparib in MBC. This study was activated in July 2019. Funding support for the clinical trial is provided by a Pfizer ASPIRE award. (NCT03990896).

Citation Format: Neelima Vidula, Nora Horick, Erin Basile, Sara Sutherland, Ruth Fax, Daniel Haber, Leif Ellisen, Hope S. Rugo, Aditya Bardia. Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: Genotyping based clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-03.