The introduction of ADCs into frontline ovarian cancer treatment creates a new challenge: conflicting biomarkers. A patient's tumor might be positive for both HER2 (an ADC target) and a BRCA mutation (a PARP inhibitor target), forcing clinicians to choose between two effective targeted therapies without clear guidance.

The B96 trial's potential approval for platinum-resistant ovarian cancer introduces a new treatment sequencing challenge. Clinicians must decide between this immunotherapy combination and the ADC mervituximab, which has a clear biomarker (foliate receptor alpha). The lack of a reliable biomarker for the B96 regimen complicates this decision-making process for patients.

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.

Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.

Unlike early ADCs requiring high biomarker expression (e.g., mirvetuximab), next-generation agents show efficacy even in low-expressing tumors. This allows for broader, "all-comer" clinical trial inclusion criteria instead of biomarker-gated entry, potentially expanding patient access to these novel therapies.

The ADC mirvetuximab is the first drug to demonstrate an overall survival benefit for platinum-resistant ovarian cancer. This groundbreaking result establishes a higher efficacy standard that subsequent therapies will likely need to meet for regulatory approval and clinical adoption, raising the bar for future drug development.

The future of GYN oncology immunotherapy is diverging. For responsive cancers like endometrial, the focus is on refining biomarkers and overcoming resistance. For historically resistant cancers like ovarian, the strategy shifts to using combinatorial approaches (e.g., CAR-NKs, vaccines) to fundamentally alter the tumor microenvironment itself, making it more receptive to an immune response.

Despite the KEYNOTE-B96 trial showing a statistically significant survival benefit, the expert's enthusiasm for adding pembrolizumab in platinum-resistant ovarian cancer is only "neutral." This hesitation stems from challenges in sequencing it with other effective therapies and uncertainty about which patient subgroups truly benefit.

Patients whose ovarian cancer progresses on the folate-targeted ADC mirvetuximab may still respond to a subsequent folate-targeted ADC with a different cytotoxic payload. This suggests that the folate receptor alpha target remains viable and that resistance may be payload-specific, opening new sequencing strategies.