A new paradigm for treating recurrent platinum-resistant ovarian cancer: synergistic mechanisms, clinical evidence, and future directions of immune checkpoint inhibitors combined with PARP inhibitors

Ovarian cancer (OC) remains the deadliest gynecologic malignancy, with a persistently high mortality rate driven largely by late-stage diagnosis and the near-inevitable development of acquired platinum resistance. The mechanisms underlying this resistance are multifaceted, encompassing enhanced DNA damage repair, increased drug efflux, and profound remodeling of the tumor immune microenvironment. In response to these challenges, combination regimens incorporating immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising therapeutic paradigm, leveraging distinct but complementary mechanisms to circumvent platinum resistance. This review systematically examines the mechanistic rationale, clinical development, and future directions of PARPi–ICI combination therapy in ovarian cancer. PARPis potentiate tumor immunogenicity by inducing DNA damage, activating the cGAS–STING pathway, and triggering immunogenic cell death, thereby converting immunologically “cold” tumors into “hot” ones and reversing the immunosuppressive milieu associated with platinum resistance. Clinical studies have demonstrated the clinically meaningful activity of this strategy across multiple disease settings. In the first-line maintenance setting, the DUO-O trial showed that the triple combination of durvalumab, olaparib, and bevacizumab significantly extended progression-free survival (PFS) in patients with homologous recombination deficiency (HRD)-positive tumors. In the platinum-resistant recurrent setting, the TOPACIO/KEYNOTE-162 study indicated that response to combination therapy correlated with DNA repair status, including HRD and BRCA mutation status. Looking forward, the optimization of biomarker-driven patient selection—integrating HRD status, immune microenvironment features, and emerging predictive factors—along with deeper investigation into resistance mechanisms, will be essential to realize the full potential of personalized treatment in ovarian cancer.