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.

The KEYNOTE-B21 adjuvant trial revealed a crucial paradox: adding pembrolizumab may worsen outcomes for mismatch repair proficient (pMMR) patients (HR 1.2), while being highly beneficial for dMMR patients. This highlights that metastatic and adjuvant settings are not equivalent.

Data from DUO-E and RUBY Part 2 trials show adding a PARP inhibitor to chemo-immunotherapy provides only a small PFS benefit. Experts are not convinced of its value, citing a lack of overall survival benefit and potential for harm.

While immunotherapy is transformational for DMMR endometrial cancer, its benefit is much smaller for the PMMR majority (two-thirds of patients). This reality requires more nuanced patient counseling and selective use in this population.

While PARP inhibitors plus immunotherapy (e.g., in the RUBY-2 trial) improved progression-free survival (PFS) in pMMR endometrial cancer, the overall survival (OS) curves crossed, showing no OS benefit. This cautionary signal suggests the combination may not be advantageous long-term and requires further investigation.

Clinical trials show a sustained overall survival benefit for upfront chemo-immunotherapy in dMMR patients, even with over 90% of the placebo group receiving immunotherapy upon progression. This demonstrates that delaying immunotherapy fails to rescue outcomes, making upfront use critical.

Despite a plausible biologic rationale, adding PARP inhibitors to chemotherapy and immunotherapy for endometrial cancer has shown minimal benefit and potential for harm. Clinicians await final overall survival (OS) data before adopting this strategy, citing a lack of convincing evidence from recent trials.

For dMMR endometrial cancer patients on combination therapy, clinicians are quicker to reduce or stop chemotherapy (like taxanes) when side effects arise. This practice reflects a growing confidence that immunotherapy is the primary driver of efficacy in this subgroup, allowing for a reduction in chemotherapy-related toxicity.

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.