Abstract 1698: Synergy with decitabine expands the utility of talazoparib: A novel therapeutic strategy for BRCA-proficient pancreatic cancer

Abstract Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have a 5-year survival rate of 13%. In those with unresectable disease, standard chemotherapy offers limited benefit, with a median survival between 8 and 12 months. Approximately 17% of patients with PDAC carry a germline or somatic mutation in the BRCA or PALB2 genes. These patients may benefit from poly (ADP-ribose) polymerase inhibitors (PARPi), which induce synthetic lethality in tumors with homologous recombination deficiency. The POLO trial showed that maintenance olaparib - a PARPi - doubled progression-free survival in patients with germline BRCA mutations and metastatic PDAC. We’ve previously reported that DNA methyltransferase inhibitors (DNMTi) can induce a “BRCAness” phenotype in other types of cancer, thus sensitizing BRCA-proficient cancer cells to PARPi. Here we explore the synergistic potential of PARPi talazoparib (TAL) and DNMTi decitabine (DAC) in pancreatic cancer cell lines and patient-derived pancreatic tumor organoids (PTOs). Methods: Synergy studies with TAL and DAC were performed in two murine (Panc02 and KPC) and three human (Capan1, SW1990, and MIA PaCa-2) pancreatic cancer cell lines with diverse genetic profiles. Of note, Capan1 harbored a BRCA2 mutation. Combination TAL+DAC treatment was performed in a dose-dependent and fixed ratio scheme, and the various degrees of synergy were determined using Chou-Talalay mathematical modeling (Compusyn). Clonogenic assays were performed with murine cell lines. Three patient-derived PTOs were treated with single agent (TAL or DAC) or combination (TAL+DAC) regimens and response was determined by MTS assay. Methylomic profiles including gene level methylation and hydroxymethylation fraction in treated and untreated PTOs were acquired using Biomodal’s Duet Multiomics Assay. Statistical analyses for clonogenic and MTS assays were performed using GraphPad Prism. Results: A synergistic inhibitory effect was observed in all pancreatic cancer cell lines when treated with TAL+DAC. The Capan1 cell line was more sensitive to TAL, as expected. Clonogenic survival assays showed a statistically significant decrease in colony numbers after treatment with the combination regimen compared to single-agent treatment. All PTOs exhibited growth inhibition when treated with DAC alone, whereas TAL alone had limited effects. The combination of TAL and DAC at low doses was more effective than either agent alone. Methylomic analysis revealed decreased methylation of key genes in DAC-treated PTOs, validating DAC’s mechanistic effects. Conclusions: The combination of TAL and DAC demonstrates synergistic cytotoxicity in pancreatic cancer cell lines and tumor organoids, suggesting potential for this treatment strategy in BRCA-mutated and BRCA-proficient PDAC. Citation Format: Zachery Keepers, Brandon Carter-Cooper, Hurley Ryan, Stephen B. Baylin, Rena Lapidus, Feyruz V. Rassool, Hem D. Shukla, Aaron T. Ciner. Synergy with decitabine expands the utility of talazoparib: A novel therapeutic strategy for BRCA-proficient pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1698.