Rethinking Treatment Intensification in Poorly Chemosensitive Ovarian Cancer: A Review.

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.