Abstract 3726: Absence of synergistic effects for PARPi and immunotherapy combinations in ex vivo 3D micro tumor assay for ovarian cancer patients
Authors: Lieke J. Ceton, Esmee Koedoot, Timothy J. Sijsenaar, Dieudonné J. van der Meer, Marta Montero Garcia, Jurrian van der Valk, Kristofer Maad, Cor de Kroon, Anne van Altena, Willemijn Vader, Judith Kroep, Nelleke Ottevanger
Journal: Cancer Research (2024)

Abstract Introduction: 50% of ovarian cancers are homologous recombination deficient (HRD), with 15% of the patients carrying a BRCA mutation. PARP inhibitors (PARPi) are designed to improve survival in HRD patients, but clinical responses to PARPi often do not match HRD status. In this study, a 3D ex vivo tumor testing platform was applied to quantify patient-specific drug responses to (combinations of) PARPi, chemo- and immunotherapies. Material and Methods: 81 patients with ovarian cancer eligible for chemotherapy were included in the trial between 2019 and 2022 in the Netherlands (IRB P18.032). Tumor clusters were isolated from ascites and solid tissue, seeded and exposed to three PARPi, standard-of-care chemotherapies and immunotherapies, both single agent and in combination. Ex vivo drug sensitivity was quantified using high-throughput 3D imaging and extraction of morphological features. Bliss scores were calculated for synergy analysis. Results: Results were generated in two weeks after sample collection. Ex vivo patient-specific response profiles were observed for all drug classes, with a small percentage of patients (7%) showing strong PARPi sensitivity reflected by strong tumor cluster shrinkage upon treatment. Significant correlation of drug sensitivity profiles was observed comparing the different PARPi between themselves, but also comparing PARPi and platinum responses. Interestingly, ex vivo sensitivity to olaparib and immunotherapy combinations demonstrated additive, but no synergistic effects (21 patients, 79 tests). In addition, olaparib responses were shown to be independent of immune responses (SEA). Conclusion: This study applied a predictive ex vivo 3D micro tumor testing platform to classify patient-specific sensitivity to (a combination of) PARPi, chemo- and immunotherapies in over 80 patients. The current dataset demonstrates the potential of ex vivo testing to identify patients that are responsive to PARPi. No synergistic effects were observed for these drugs in combination with immunotherapies. Discussion: Evaluation of PARPi responses in a functional 3D micro tumor assay could support identification of responsive patients prior to treatment. Distinct responses were observed for PARPi and immunotherapies. No synergistic but additive effects were measured, suggesting that ovarian cancer patients could benefit from PARPi and immunotherapies. Correlation of clinical and ex vivo drug responses to PARPi in combination with available HRD tests will further validate the platform for predicting patient clinical outcome. Citation Format: Lieke J. Ceton, Esmee Koedoot, Timothy J. Sijsenaar, Dieudonné J. van der Meer, Marta Montero Garcia, Jurrian van der Valk, Kristofer Maad, Cor de Kroon, Anne van Altena, Willemijn Vader, Judith Kroep, Nelleke Ottevanger. Absence of synergistic effects for PARPi and immunotherapy combinations in ex vivo 3D micro tumor assay for ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3726.