PARP inhibitor maintenance in first-line ovarian cancer therapy: emerging standards and strategies to overcome resistance.

Maintenance therapy has become a central component of first-line treatment for advanced epithelial ovarian cancer, and poly(ADP-ribose) polymerase (PARP) inhibitors now occupy a pivotal position in this setting. Their greatest benefit is observed in tumors with BRCA1/2 mutations or broader homologous recombination deficiency (HRD), where synthetic lethality can be therapeutically exploited. However, clinical use of PARP inhibitors in the frontline setting has also raised new questions regarding optimal biomarker selection, treatment duration, combination strategies, long-term safety, and management of disease that recurs after PARP exposure. In this review, we summarize the evidence supporting first-line PARP inhibitor maintenance across biomarker-defined subgroups, with particular emphasis on BRCA-mutated and HRD-positive disease. We then examine emerging strategies designed to extend benefit or overcome resistance, including combinations with anti-angiogenic agents, immune checkpoint inhibitors, and next-generation DNA damage response (DDR) inhibitors. Mechanisms of resistance are discussed in a translational framework that includes restoration of homologous recombination, replication-fork protection, altered PARP1 trapping, and adaptive rewiring of the DDR network. Finally, we outline practical clinical approaches to post-PARP management and highlight future priorities, including dynamic biomarkers, rational sequencing, and more individualized maintenance strategies. Taken together, current evidence supports a biomarker-driven use of frontline PARP maintenance while underscoring the need for resistance-aware treatment planning and more precise integration of combination approaches.