Use of multiplexed functional profiling to reveal antiproliferative activity of PARP inhibitors missed by cytotoxicity-only assays in primary ovarian cancer tissues.

e15123 Background: PARP inhibitors (PARPi) are primarily used as maintenance therapy in ovarian cancer, where clinical benefit often reflects disease stabilization rather than tumor regression. Most ex-vivo drug response assays rely on cytotoxicity alone, potentially overlooking biologically relevant antiproliferative effects. We sought to characterize cytotoxic and antiproliferative responses of PARP inhibitors in primary ovarian cancer tissues and to assess functional concordance between olaparib, niraparib, and rucaparib. Methods: Primary ovarian cancer specimens were processed in a CLIA-certified laboratory to generate patient-derived microtumors preserving their native tumor architecture. Ex-vivo responses to olaparib, niraparib, and rucaparib were assessed using multiplexed cytotoxicity and anti-proliferation assays. Pearson correlation coefficients with 95% confidence intervals were calculated to evaluate associations between cytotoxicity and antiproliferation, as well as the concordance of those PARP inhibitors within this class. Results: Across 18 tumors, cytotoxic and antiproliferative effects were weakly correlated or uncorrelated for individual PARP inhibitors and for the drug class overall (overall r = −0.04, p = 0.78). Multiple specimens demonstrated marked suppression of proliferation ( > 50%) with minimal cytotoxicity ( < 20%). Correlations of PARP inhibitors were only moderate for both cytotoxic and antiproliferative responses (PARP to PARP r ranging 0.35–0.75), indicating incomplete functional overlap within the class. Thus, while median antiproliferative effects were comparable across PARP inhibitors there was substantial functional drug response variability between the tumors. Conclusions: PARP inhibitor activity in primary ovarian cancer tissues is not adequately characterized by cytotoxicity alone. Instead, multiplexed functional profiling that includes biologically relevant antiproliferative effects may be necessary to better capture maintenance-associated disease stabilization with PARP inhibitors. Furthermore, the only moderate concordance of antiproliferative activity across individual PARP inhibitors suggests that the presumed class effect may be less uniform than generally assumed, warranting further investigation, ideally in conjunction with multiplexed antiproliferative functional profiling, to demonstrate its clinical relevance.