Abstract B138: Pharmacodynamics-driven phase 2 trial of talazoparib in patients with advanced solid tumors and aberrations in genes involved in DNA damage response

Abstract

Abstract Background: Talazoparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) with increased trapping of PARP-DNA complexes compared to other PARPi in clinical development. Talazoparib has single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways, and has FDA-approved indications in advanced BRCA-mutated and HER2-negative breast cancer and in homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer in combination with enzalutamide. This pilot study evaluated the pharmacodynamic (PD) effects of talazoparib on DNA damage response (DDR) markers in tumor biopsy tissue in both patients (pts) who are PARPi-naïve and pts who have received prior PARPi other than talazoparib to investigate for potential differential PARPi PD responses in DNA replication stress. Methods: We are conducting a multicenter phase 2 trial in adult pts with eligible deleterious germline or somatic mutations in BRCA1/2 or genes involved in DDR including ATM, ARID1A, IDH1, BAP1, ATR, CHK2, and PALB2. Pts were enrolled and assessed in two cohorts: 1) pts who were PARPi-naïve, and 2) pts who were treated with and had documented progression on a PARPi other than talazoparib. Talazoparib is administered orally at a dose of 1000 µg/day (D) in 28 D cycles (C). The primary objective is determining the replication stress PD effect of talazoparib as evaluated by activation of Rad51 combined with a lack of γH2AX activation. Paired tumor biopsies (baseline and C2D1) will be analyzed for DDR markers (γH2AX, pNBS1, and Rad51) by IFA. Responses and adverse events (AEs) are defined by RECIST 1.1 and CTCAE v5.0, respectively. Results: The PARPi-naïve cohort had 15 pts enrolled with a median age of 58 years (range 38-76) and median prior lines of systemic therapy of 2 (range 1-5). The PARPi-treated cohort had 8 pts enrolled with a median age of 72 years (range 35-85) and median prior lines of systemic treatment of 5.5 (range 1-10). A total of 11 sets of pre-treatment and post-treatment tumor biopsies have been received to date and analyses of DDR markers are ongoing. Of 11 pts in the PARPi-naïve cohort evaluable for response, 6 pts had stable disease (SD) as best response with 2 pts (nasal cavity cancer with ARID1A alteration, bile duct cancer with IDH1 alteration) who received talazoparib for ≥ 6 C. Of 7 pts in the PARPi-treated cohort evaluable for response, 4 pts had SD as best response. Treatment-related AEs of ≥ grade 2 with ≥ 5% incidence included anemia (n=10, 43.5%), leukopenia (n=7, 30.4%), lymphopenia (n=6, 26.1%), thrombocytopenia (n=6, 26.1%), and neutropenia (n=4, 17.4%). Conclusions: Study enrollment and analyses of PD DDR markers in paired tumor biopsies are both ongoing with data to be presented at the conference. No responses have been observed to date, which may be due to prior therapies, tumor histologies, mutational selection or dose delivered with further characterization anticipated via PD DDR marker data. Citation Format: Brian Ko, Geraldine H O'Sullivan Coyne, Abdul Rafeh Naqash, Thomas J George, David DeRemer, Larry Rubinstein, Jennifer Zlott, Deborah Wilsker, Donna Ketchum, Stephanie Runkle, Katherine V Ferry-Galow, Ralph E Parchment, Naoko Takebe, Sarah Shin, Andrea R Voth, Jiuping Ji, S. Percy Ivy, James H Doroshow, Alice P Chen. Pharmacodynamics-driven phase 2 trial of talazoparib in patients with advanced solid tumors and aberrations in genes involved in DNA damage response [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B138.