Beyond Platinum Resistance: Reconsidering Platinum Sensitivity as a Dynamic Phenotype in Ovarian Cancer

Platinum-based chemotherapy remains a key treatment for epithelial ovarian cancer, but platinum resistance is a major cause of treatment failure and mortality. Traditionally, platinum resistance has been defined by the interval between the last platinum treatment and disease progression, with progression within six months generally classified as platinum-resistant. This six-month platinum-free interval has long provided a useful framework for treatment selection. However, growing preclinical and clinical evidence suggests that this interval should not be treated as a strict biological boundary. Platinum susceptibility can change as tumors evolve, with some tumors retaining residual sensitivity while others develop stable or potentially modifiable resistance mechanisms. These mechanisms include restoration of homologous recombination, altered DNA-damage tolerance, epigenetic regulation, changes in platinum transport and detoxification, adaptive survival signaling, and alterations in cell-death pathways. Some resistance mechanisms are relatively stable, whereas others may remain biologically plastic and potentially amenable to therapeutic modification. This distinction has important implications for platinum rechallenge. Responses to platinum reintroduction in selected patients previously classified as platinum-resistant indicate that the six-month interval does not fully capture the biology of platinum responsiveness. However, renewed clinical activity after rechallenge should not automatically be interpreted as biological resensitization. True resensitization requires evidence that a defined resistance mechanism has been modified and that this alteration increases platinum susceptibility. Preclinical studies have identified multiple strategies to modify platinum-resistance pathways, but clinical translation remains limited. This perspective therefore proposes that platinum resistance should be understood as a clinically defined phenotype encompassing biologically heterogeneous states, some of which may be stable and others potentially reversible. Recognizing this distinction has implications for biomarker development, treatment selection, trial design, and interpretation of platinum rechallenge. Prospective studies incorporating longitudinal tumor profiling and functional assessments of platinum susceptibility may ultimately identify patients in whom platinum activity can be therapeutically restored.