Harnessing synergy: Innovative combinations to overcome PARP inhibitor resistance in cancer treatment.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized precision oncology over the past decade by using synthetic lethality to precisely target cancers with defective homologous recombination repair (HRR) pathways. Initially explored as chemosensitizers to potentiate DNA-damaging agents, PARPi have undergone significant clinical development and are now approved as monotherapies for HRD-driven malignancies, particularly in BRCA-mutant ovarian, breast, and prostate cancer, highlighting their ability to provide survival advantages in populations defined by biomarkers. Despite these revolutionary accomplishments, two persistent obstacles hinder wider clinical utility: the nearly universal emergence of acquired resistance and the limited patient population that benefits from long-term responses to monotherapy. These challenges have catalyzed the development of rational combination strategies exploiting collateral molecular dependencies to overcome intrinsic therapeutic limitations. Here we analyze the evolving landscape of PARPi-based combination therapies through three conceptual lenses: mechanistic interrogation of synthetic lethal networks beyond canonical HRR defects, clinical translation of combinatorial vulnerabilities across tumor lineages, and critical appraisal of therapeutic ceilings through pharmacodynamic biomarkers. By bridging preclinical rationales with clinical validation data, we propose a translational framework to optimize combinatorial therapeutic indices, ultimately guiding rational clinical development and precision medicine implementation.