The treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.

The traditional six-month timeframe for defining platinum sensitivity is being challenged. A growing theory suggests that tumors progressing while on a PARP inhibitor have a distinct biology that responds poorly to subsequent platinum, indicating a potential need to move directly to therapies like ADCs.

The traditional practice of classifying recurrent ovarian cancer as 'platinum-sensitive' or 'platinum-resistant' based on a six-month treatment-free interval is rapidly becoming obsolete. The introduction of maintenance therapies like PARP inhibitors is changing tumor biology and response patterns, suggesting this simple time-based distinction no longer adequately reflects the clinical reality.

Real-world data shows that in platinum-sensitive ovarian cancer patients who have progressed on PARP inhibitors, subsequent platinum-based chemotherapy has a surprisingly low response rate of only 20%. This quantifies a significant opportunity for highly active ADCs to potentially replace platinum in this growing patient population.

The widespread use of PARP inhibitors has altered tumor biology in platinum-sensitive ovarian cancer. A recent meta-analysis of heavily pretreated patients, 97% of whom had prior PARP inhibitor exposure, revealed an objective response rate to subsequent therapy of only 17%—far lower than historical expectations, highlighting a critical unmet clinical need.

Although the overall trial was negative, exploratory analysis of the AGO-OV-229 study suggested patients previously treated with Bevacizumab derived more benefit from Atezolizumab, hinting at a potential synergy worth further investigation.

The selection between PARP inhibitors like olaparib and niraparib is not one-size-fits-all. It's a personalized decision based on patient preference for dosing frequency (once vs. twice daily), tolerance for side effects like hypertension, and potential drug-drug interactions.

While retreating with a PARP inhibitor after a long progression-free interval is a viable strategy for patients with BRCA mutations, experts express caution and hesitancy in applying the same approach to patients who are HRD-deficient but BRCA wild-type, partly due to changing FDA labels.

Historically, therapies for platinum-resistant ovarian cancer were so ineffective that the order of administration was irrelevant. With the advent of multiple active ADCs, the concept of treatment sequencing and potential cross-resistance based on payloads or targets has become a critical, and entirely new, clinical consideration for this disease.