Endometrial Cancer Therapies

Epidemiology & Impact

Endometrial cancer is the most common gynecologic malignancy in the United States, with approximately 68,420 new cases and 13,550 deaths expected in 2025. Incidence has been rising approximately 1% per year, driven largely by increasing obesity rates, as excess adipose tissue produces estrogen that stimulates endometrial proliferation. The disease predominantly affects postmenopausal women, with a median age at diagnosis of 63 years. A concerning trend is the rising mortality rate, increasing approximately 1.5% annually, partly reflecting the growing proportion of aggressive histologic subtypes (serous, clear cell) and advanced-stage diagnoses, particularly among Black women who have mortality rates nearly double those of White women.

Molecular Biology & Biomarkers

Endometrial cancer is classified into four molecular subtypes by The Cancer Genome Atlas (TCGA), now incorporated into clinical practice: POLE ultramutated (excellent prognosis regardless of grade), microsatellite instability-high/mismatch repair deficient (dMMR, approximately 30% of cases, favorable prognosis, highly immunotherapy responsive), copy number low/p53 wild-type (intermediate prognosis), and copy number high/p53 abnormal (poor prognosis, enriched in serous histology). This molecular classification has become clinically essential because it overrides traditional histologic classification in guiding treatment. dMMR/MSI-H status identifies patients who derive exceptional benefit from checkpoint immunotherapy and also flags potential Lynch syndrome, requiring germline genetic testing. HER2 amplification occurs in approximately 25-30% of serous endometrial cancers and is a therapeutic target.

Evolving Treatment Landscape

The treatment paradigm for advanced endometrial cancer has been dramatically reshaped by immunotherapy. The RUBY trial demonstrated that adding dostarlimab to carboplatin-paclitaxel significantly improved progression-free and overall survival in the frontline setting, with the most pronounced benefit in dMMR tumors (3-year PFS of 61.4% versus 15.7%). Similarly, the NRG-GY018 trial showed that pembrolizumab plus chemotherapy significantly improved PFS in both dMMR and proficient MMR endometrial cancers. These results have established immunotherapy-chemotherapy combinations as the new first-line standard. Lenvatinib plus pembrolizumab remains the standard second-line regimen for pMMR tumors.

EMA-Approved Therapies for Endometrial Cancer

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key approvals with comparative timelines to FDA, demonstrating regulatory differences between regions.

For complete European approval details, visit ema.europa.eu ↗