The GOG-B21 trial found that while adding pembrolizumab to chemotherapy benefits the dMMR subgroup, it paradoxically leads to worse outcomes in the pMMR subgroup. This highlights the critical need for molecular testing to avoid potential harm.

Based on translational data from the RUBY trial, experts are most cautious about recommending frontline checkpoint inhibitors for patients in the "No Specific Molecular Profile" (NSMP) subgroup of pMMR endometrial cancer, suggesting this group may not benefit.

Despite multiple clinical trials, adding checkpoint inhibitors to frontline therapy for ovarian cancer has not demonstrated a proven survival benefit. The role of immunotherapy in this setting remains confined to rare subsets like DMMR or TMB-high tumors, and it is not standard practice for the general population.

Even when neoadjuvant immunotherapy achieves an excellent systemic response in MSI-high endometrial cancer, residual disease frequently persists within the uterus. This finding cautions against forgoing hysterectomy based on imaging or systemic response alone.

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.

With dostarlimab, pembrolizumab, and durvalumab showing similar efficacy in endometrial cancer, the final selection often depends on non-clinical factors like clinician familiarity, specific trial criteria, or insurance company mandates.

The rationale for adding PARP inhibitors to immunotherapy in endometrial cancer is to induce DNA damage and cell death. This process creates neoantigens, potentially making tumors more recognizable and vulnerable to the immune system, especially in PMMR patients.

Disparate clinical trial results in endometrial cancer suggest a mechanistic difference between immunotherapy targets. PD-1 inhibitors (dostarlimab, pembrolizumab) have shown pronounced responses, whereas the PD-L1 inhibitor atezolizumab did not, indicating that targeting the PD-1 receptor may be a more robust strategy in GYN cancers.

While checkpoint inhibitors are standard for dMMR endometrial cancer, a clear clinical boundary is emerging for the pMMR subgroup. Based on trial data showing no benefit for fully resected disease (e.g., B21 trial), oncologists are not offering immunotherapy to pMMR patients without measurable disease, avoiding significant toxicity without proven efficacy.