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.

After numerous failed trials suggested immunotherapy was ineffective in ovarian cancer, the KEYNOTE B96 study marks a turning point. Combining pembrolizumab with chemotherapy showed statistically significant improvements in both progression-free and overall survival in platinum-resistant patients, reviving the entire therapeutic class for this disease.

The arrival of multiple effective, biomarker-linked therapies for diseases like ovarian cancer creates a new, complex challenge for oncologists. No longer a matter of choosing the single best next option, treatment has become a strategic game of sequencing, requiring physicians to think "five plays ahead" to maximize the benefit of all available drugs over the patient's lifetime.

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 decision between new regimens in platinum-resistant ovarian cancer—relicorolant/nab-paclitaxel vs. pembrolizumab/paclitaxel—hinges on the patient's need for bevacizumab. If bevacizumab is required for symptomatic disease, the relicorolant combination is off the table.

For very high-risk premenopausal patients (e.g., 4+ positive nodes), clinicians may recommend continuing ovarian function suppression beyond the standard 5 years, sometimes advocating for permanent oophorectomy. This is based on clinical experience and data suggesting a more durable blunting of recurrence risk with permanent ovarian ablation.

For HRD-positive ovarian cancer, a strong initial response to platinum chemotherapy may justify using a PARP inhibitor alone for maintenance. A weaker response, however, suggests adding bevacizumab for a potentially greater benefit, using clinical response as a key decision-making tool.

Despite concerns about cross-resistance from breast cancer data, experts would consider sequencing ADCs with the same payload (e.g., deruxtecan). The rationale is that even a diminished response rate (e.g., 30%) is still significantly better than the 15% seen with standard single-agent cytotoxics.

A promising future strategy for ovarian cancer involves combining two different ADCs. The key to this approach is selecting agents with distinct payloads (e.g., an anti-microtubulin and a TOPA-1 inhibitor) whose side effect profiles do not overlap. This could maximize anti-tumor efficacy while maintaining a manageable toxicity burden for patients, offering a novel combination paradigm.