Platinum cross-resistance after first-line PARPi maintenance in ovarian cancer: a review and proposed redefinition of platinum resistance.

Poly(ADP-ribose) polymerase inhibitors (PARPis) as first-line maintenance therapy have significantly prolonged progression-free survival (PFS) in patients with advanced ovarian cancer and have become a standard of care. However, PARPis and platinum agents share DNA damage repair pathways, and preclinical and clinical studies suggest the existence of cross-resistance mechanisms. With the widespread use of first-line PARPi maintenance, whether it compromises the efficacy of subsequent platinum-based chemotherapy and whether the traditional definition of platinum resistance (treatment-free interval <6 months) needs to be revisited have emerged as urgent clinical issues. This review systematically summarizes the molecular mechanisms of cross-resistance, focuses on clinical evidence from the first-line maintenance setting (including real-world data and subgroup analyses of randomized controlled trials), and incorporates relevant updates from the National Comprehensive Cancer Network (NCCN) guidelines. Available evidence indicates that after first-line PARPi maintenance, patients have shorter subsequent time to next treatment (TTNT) and treatment-free interval (TFI). In the homologous recombination deficiency (HRD)-negative subgroup, overall survival point estimates are consistently >1 (PRIMA 1.09, PAOLA-1 1.19; 95% CIs crossed 1), consistent with the direction of the cross-resistance hypothesis. Based on these findings, we propose that the traditional definition of platinum resistance should be revised to incorporate prior PARPi exposure and molecular biomarkers. We also recommend caution when re-challenging with platinum after PARPi progression, prioritizing non-platinum regimens or clinical trials. Future prospective studies directly comparing different treatment strategies after first-line PARPi progression are urgently needed.