Functional biomarkers complementing static BRCA/HRD testing for dynamic PARP inhibitor therapy in ovarian cancer: a...

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of high-grade serous ovarian cancer (HGSOC). Yet, current treatment decisions remain almost exclusively guided by static BRCA/homologous recombination deficiency (HRD) genotyping. This paradigm is increasingly challenged by a profound eligibility-benefit gap: real-world data show 93.4% of patients are PARPi-eligible, but only 22.0% achieve meaningful 2-year progression-free survival benefit, compounded by 10-30% HRD test failure rates, inability to capture dynamic resistance evolution, and negligible predictive value in the ~50% of HGSOC that are homologous recombination-proficient. This narrative review, based on literature up to June 2026, systematically evaluates functional biomarkers that complement BRCA/HRD testing by assessing real-time tumor biology. To our knowledge, this is the first review to integrate these biomarkers into a unified whole-disease-course framework accounting for evidence level, assay cost, and global resource setting. RAD51 immunohistochemistry directly visualizes homologous recombination repair capacity, achieving 95% accuracy in predicting PARPi response in preclinical patient-derived xenograft models and demonstrating robust predictive value in prospective clinical cohorts. The KELIM model, derived from early CA-125 kinetics and evaluated in >12,000 patients within prospective trial and registry datasets, provides a no-additional-assay-cost, tissue-independent readout of chemosensitivity with potential for broad, low-cost global deployment. Circulating tumor DNA enables noninvasive longitudinal monitoring of resistance, potentially preceding radiographic progression by weeks to months. Exploratory immune and artificial intelligence-based multimodal markers further refine response stratification. We propose deployment of these biomarkers at four critical clinical nodes-diagnosis, post-chemotherapy, maintenance, and progression-to guide therapy selection dynamically. By transitioning from static genotype-based eligibility to real-time functional phenotyping, this integrated strategy aims to close the eligibility-benefit gap and advance adaptive precision oncology for ovarian cancer globally. As a narrative review, this work aims to offer forward-looking conceptual frameworks and stimulate future research rather than to establish high-level clinical evidence or formal guidelines.