Rethinking Treatment Intensification in Poorly Chemosensitive Ovarian Cancer

Importance Despite the integration of bevacizumab and poly(ADP-ribose) polymerase inhibitors into first-line treatment of advanced high-grade serous ovarian cancer, survival remains poor for the substantial subset of patients whose tumors respond insufficiently to platinum-based chemotherapy and who, therefore, frequently do not achieve complete cytoreductive surgery (the 2 red flags population). This Review examines the rationale, current evidence, and emerging strategies for systemic treatment intensification—or chemosensitization—aimed at improving tumor response before initiating maintenance therapy. Observations Achieving minimal residual disease before maintenance depends on 2 key determinants: surgical completeness and intrinsic tumor chemosensitivity. Pragmatic indicators of chemosensitivity—KELIM (modeled cancer antigen 125 elimination rate constant K), pathological chemotherapy response score, and radiologic response—are now cited in European Society for Medical Oncology–European Society of Gynaecological Oncology and American Society of Clinical Oncology guidelines, while BRCA /homologous recombination deficiency status may not reliably predict neoadjuvant carboplatin-paclitaxel response. Across post hoc analyses of phase 3 trials (ICON-7, GOG-0218, ICON-8, ICON-8B, VELIA, and IMagyn050), patients with poorly chemosensitive disease may have derived greater benefit from intensification strategies. Weekly dose-dense paclitaxel was associated with improved survival in the 2 red flags subgroup of ICON-8. Bevacizumab, added either to standard postoperative chemotherapy or to neoadjuvant dose-dense chemotherapy, showed signals of greater benefit on both progression-free and overall survival in high-risk and poorly chemosensitive subsets. In contrast, poly(ADP-ribose) polymerase inhibitor and immune checkpoint inhibitor combinations showed meaningful activity only in selected subgroups, supporting further evaluation of innovative DNA repair–targeting agents and immunotherapeutic approaches in these populations. Conclusions and Relevance Early identification of poorly chemosensitive advanced high-grade serous ovarian cancer enables a response-adapted first-line strategy in which treatment intensification is selectively offered to patients most likely to benefit—an approach now being prospectively evaluated in the phase 3 SALVOVAR and phase 1/2 RegeNovar trials. This framework provides a clinically actionable platform to test novel therapies aimed at increasing complete interval cytoreduction rates and improving survival in a population with otherwise limited options.