Abstract 2154: Modeling olaparib resistance in prostate cancer PDXs to elucidate PARP inhibitor escape mechanisms.

Abstract Patient-derived xenografts (PDXs) are essential preclinical tools for modeling prostate cancer (PCa) biology and assessing therapeutic responses. Over the past years, we have established and comprehensively characterized a panel of 15 prostate cancer PDX models that recapitulate the histological and molecular heterogeneity of human disease. While PARP inhibitors such as olaparib provide clinical benefit to patients harboring BRCA1/2 mutations or homologous recombination deficiency (HRD), resistance inevitably emerges and remains a major clinical challenge. Here, we present insights that pave the way for characterizing mechanisms of PARP inhibitor resistance and identifying strategies to circumvent PARPi escape using our panel of PCa PDX models. Therapeutic responses to olaparib were evaluated across the biobank, alongside assessment of homologous recombination repair (HRR) status. Most PDX models displayed intrinsic resistance, whereas three showed marked sensitivity. Notably, a neuroendocrine prostate cancer (NEPC) PDX harboring DNA damage-repair alterations exhibited pronounced olaparib sensitivity, providing the first preclinical evidence supporting PARP inhibitor activity in a neuroendocrine context. These three sensitive models were then exposed to chronic treatment until tumor recurrence, generating acquired olaparib-resistant derivatives. Resistant PDXs were compared with their isogenic sensitive counterparts through histopathological analysis and transcriptomic and genomic profiling, with a focus on DNA repair and compensatory pathways. Multi-omic analyses indicate involvement of mechanisms such as partial restoration of homologous recombination and activation of alternative DNA repair pathways. Overall, this unique PCa PDX panel, together with the newly generated olaparib-resistant derivatives, constitutes a valuable preclinical resource for deciphering PARP inhibitor resistance mechanisms and informing the development of next-generation therapeutic combinations for prostate cancer. Citation Format: Nadège BIDAN, Claire BERAUD, Emilie INDERSIE, Marie TAVERNIER, Clementine KRUCKER, Eric POTIRON, Philippe LLUEL, Olivier DÉAS. Modeling olaparib resistance in prostate cancer PDXs to elucidate PARP inhibitor escape mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2154.