Several immunotherapies for advanced endometrial cancer are US Food and Drug Administration (FDA) approved for tumors with molecular features such as mismatch repair deficiency (dMMR). However, some immunotherapy regimens may also be appropriate for patients with mismatch repair proficiency (pMMR). A subgroup analysis from the DUO-E trial presented at the recent Society of Gynecologic Oncology (SGO) 2025 Annual Meeting on Women’s Cancer explored this idea.

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Following this presentation, featured expert Bradley J. Monk, MD, FACS, FACOG, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Dr Monk’s clinical perspectives on these findings are presented here.

The endometrial cancer staging system has undergone several iterations, evolving from clinical to pathologic characteristics, and now also incorporating molecular characteristics. There is a relationship between histology and molecular findings. For example, serous endometrial cancer is commonly TP53 mutated and has a poor prognosis, which helps inform the choice of treating with more intensive therapy. For patients whose endometrial cancer is POLE mutated, which is highly associated with a better prognosis, it may be possible to de-escalate treatment.

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Some molecular characteristics are already being used to guide the selection of treatment for endometrial cancer. For example, pembrolizumab monotherapy is FDA approved for patients with microsatellite instability–high (MSI-H) or dMMR advanced endometrial carcinoma progressing after systemic therapy based on the results of the phase 2 KEYNOTE-158 trial. Additionally, dostarlimab monotherapy is FDA approved for recurrent or advanced dMMR endometrial cancer after progression on or after a platinum-containing regimen based on the results of the phase 1 GARNET trial. Finally, the combination of lenvatinib and pembrolizumab is FDA approved for patients with advanced endometrial cancer that is not MSI-H or dMMR after progression following prior systemic therapy based on the results of the phase 3 Study 309/KEYNOTE-775.

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2024 was an amazing year for immunotherapy approvals for advanced endometrial cancer. For example, in April 2024, trastuzumab deruxtecan received accelerated FDA approval for HER2+ solid tumors after prior systemic treatment based on the results of the phase 2 DESTINY-PanTumor02 trial and other studies. Moreover, in June 2024, the FDA granted approval to the combination of pembrolizumab and chemotherapy for patients with endometrial cancer, independent of molecular characteristics, based on the results of the phase 3 NRG-GY018/KEYNOTE-868 trial. The combination of durvalumab and chemotherapy for dMMR endometrial cancer was also FDA approved in June 2024 based on the results of the phase 3 DUO-E trial. And, finally, in August 2024, the indication for dostarlimab plus chemotherapy was expanded to include patients without dMMR and MSI-H endometrial cancer based on the results of the phase 3 RUBY trial.

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The benefit of immunotherapy in the frontline treatment of endometrial cancer has been established in dMMR disease, but its efficacy is more controversial in pMMR disease. At the SGO 2025 Annual Meeting on Women’s Cancer, Kathleen N. Moore, MD, MS, gave a very nice presentation on a subgroup analysis of patients with pMMR disease from the DUO-E trial. The post hoc exploratory analysis suggested that the addition of olaparib maintenance to durvalumab and chemotherapy may help enhance the progression-free survival benefit offered by chemotherapy alone in patients with pMMR endometrial cancer.