Following the Keynote B21 trial, clinicians have become more selective with adjuvant immunotherapy in endometrial cancer. The study showed minimal benefit for pMMR patients and less impressive gains overall in its lower-risk population compared to advanced disease trials. This has led to a practice of reserving adjuvant chemo-IO primarily for stage 3 dMMR patients.

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.

Potent responses to chemo-immunotherapy are promoting a shift toward neoadjuvant treatment for advanced endometrial cancer. Waiting six cycles often achieves a response sufficient to allow for a minimally invasive hysterectomy instead of a more extensive primary debulking surgery.

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.

Clinicians anecdotally report that immunotherapy is changing the pattern of recurrence in endometrial cancer. Instead of widespread disease, patients often develop isolated recurrences in a single location. This shift allows for the use of local therapies, like radiation, to treat the single spot while continuing the effective systemic immunotherapy.

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.

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.

Even in elderly or frail patients with MSI-high endometrial cancer, the rapid and effective tumor response from combination chemotherapy and immunotherapy often improves quality of life so significantly that it's the preferred approach over single-agent IO.

Unlike other cancers, re-treating with immunotherapy after recurrence is considered a viable strategy for dMMR endometrial cancer. Experts theorize that these tumors are constantly evolving and may benefit from a "re-education" of the immune system, challenging the conventional wisdom that progression on a drug class means permanent resistance.