Adaptive responses in a PARP inhibitor window of opportunity trial illustrate limited functional interlesional heterogeneity and potential combination therapy options

Abstract

Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.