Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, with approximately 67,000 new cases estimated in 2024. Mortality from EC is rising, and it was projected to surpass ovarian cancer as the deadliest gynecologic malignancy. This increasing burden is driven by a growing proportion of high-risk histologic subtypes including serous carcinoma, clear cell carcinoma, and carcinosarcoma, which are typically diagnosed at advanced stages and carry poor prognoses.
Historically, treatment options for advanced and recurrent EC have been limited. The backbone of therapy has been carboplatin and paclitaxel chemotherapy since GOG-0209 established this regimen in 2012, but median overall survival remained under two years. Patients who progress on first-line chemotherapy face an especially challenging treatment landscape with few effective subsequent options.
Racial disparities compound the problem. Black women have a 3 to 4-fold higher rate of serous carcinoma and carcinosarcoma compared to White women, meaning these aggressive subtypes disproportionately affect minority populations. The review examines recent practice-changing advances across immunotherapy, targeted agents, antibody-drug conjugates, and hormonal therapies that are reshaping treatment paradigms.
The 2013 Cancer Genome Atlas (TCGA) study fundamentally changed how endometrial cancer is understood by identifying four molecular subgroups: POLE hypermutated, microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR), copy number low (TP53 wildtype), and copy number high (TP53 abnormal). Each subgroup exhibits distinct genomic patterns, treatment responses, and prognoses.
To make molecular classification clinically practical, the ProMisE algorithm was developed using formalin-fixed paraffin-embedded specimens and standard immunohistochemistry techniques rather than the costly fresh-specimen genomics required by the original TCGA method. This pragmatic tool evaluates MMR protein status, POLE mutations, and TP53 expression to classify tumors into the four subgroups.
The International Federation of Gynecology and Obstetrics (FIGO) updated its staging system in 2023 to incorporate TCGA molecular classification, allowing certain molecular subgroups to upstage or downstage a patient's disease. The PORTEC-3 and GOG-258 trials provided retrospective validation that molecular subgroups predict treatment response differently, supporting the clinical utility of this approach.
Despite progress, challenges remain in making molecular testing globally accessible. DNA sequencing for POLE status is costly, and the development of affordable alternatives such as quantitative PCR is essential for widespread implementation, particularly in low-resource settings.
Pembrolizumab was the first immune checkpoint inhibitor to demonstrate durable activity in dMMR endometrial cancer, achieving a 48% objective response rate in the KEYNOTE-158 study and earning accelerated FDA approval for recurrent dMMR EC. The subsequent NRG GY-018 phase 3 trial showed that adding pembrolizumab to carboplatin and paclitaxel chemotherapy reduced the risk of disease progression or death by 70% in dMMR patients compared to placebo.
Dostarlimab showed similar efficacy in the RUBY Part 1 trial, with a 72% reduction in risk of progression or death in dMMR tumors when combined with chemotherapy, and an overall survival benefit of 44.6 months compared to 28.2 months with chemotherapy alone. The FDA approved dostarlimab for all-comer advanced or recurrent EC in August 2024, expanding treatment beyond just the dMMR population.
The ATTEND trial evaluated atezolizumab with chemotherapy and found a 64% reduction in progression risk for dMMR patients, though it has not yet received FDA approval. Across all major phase 3 immunotherapy trials, the benefit was consistently strongest in dMMR tumors, with hazard ratios ranging from 0.29 to 0.42 for progression-free survival in this subgroup.
For pMMR patients, immunotherapy still provides a more modest but real benefit. Pembrolizumab is now NCCN-recommended for all advanced or recurrent EC regardless of MMR status, based on the PFS improvements seen in the pMMR subgroup across multiple trials.
The DUO-E trial tested durvalumab alone or with olaparib added to chemotherapy in advanced or recurrent EC. In the overall population, the durvalumab plus olaparib arm achieved a 45% reduction in disease progression risk compared to control. In patients with homologous recombination repair mutations (HRRm), the combination reduced progression risk by 70%, suggesting a biologically driven synergistic effect.
Overall survival data presented at the SGO 2024 conference showed a 41% reduction in risk of death with the addition of olaparib to durvalumab, with the dMMR subgroup showing a 66% reduction. However, there was no statistically significant OS improvement in the pMMR population, and durvalumab with chemotherapy is currently approved in the US only for the dMMR population.
The RUBY Part 2 trial evaluated dostarlimab plus niraparib maintenance and demonstrated a 40% decrease in disease progression across the overall population. The rationale for combining PARP inhibitors with immunotherapy stems from preclinical data showing PARP inhibitors can upregulate PD-L1 expression, potentially enhancing immune checkpoint blockade efficacy while reducing resistance.
Lenvatinib plus pembrolizumab became an important second-line option for pMMR recurrent EC after KEYNOTE-775 showed improved PFS (6.6 vs 3.8 months) and OS compared to chemotherapy, earning FDA approval in July 2021. However, the LEAP-001 trial found this combination did not outperform standard chemotherapy as a first-line treatment, limiting its use to the recurrent setting.
HER-2 targeting has emerged as a key strategy for biomarker-driven therapy. Trastuzumab added to chemotherapy improved PFS and OS in HER2-positive serous EC, while trastuzumab deruxtecan (T-DXD) achieved a 57.5% overall response rate in HER2-expressing EC patients in the DESTINY-PanTumor02 trial. T-DXD received agnostic FDA approval in 2024 for all HER2 3+ solid tumors.
Novel targets continue to expand the treatment armamentarium. Selinexor, an XPO1 inhibitor, showed particular promise for TP53 wildtype pMMR tumors in the SIENDO trial, with long-term PFS of 28.4 vs 5.2 months in this subgroup. TROP-2 directed antibody-drug conjugates including sacituzumab govitecan showed early activity in heavily pretreated EC patients, with phase 3 trials now underway.
These biomarker-driven approaches represent a shift toward treating EC based on molecular profile rather than histology alone, with different agents targeting specific vulnerabilities in dMMR, pMMR, HER2-positive, and TP53-wildtype tumors.
Estrogen receptor-positive endometrioid EC represents a population amenable to hormonal therapy, particularly after progression on other treatments. Estrogen activates the PI3K/AKT/mTOR and RAS/RAF/MEK pathways to drive cell proliferation, and these tumors frequently harbor PTEN mutations that further activate these growth signaling cascades, creating multiple potential therapeutic targets.
The PALEO trial evaluated palbociclib (a CDK 4/6 inhibitor) combined with letrozole in ER-positive recurrent or advanced EC and demonstrated significantly improved PFS of 8.3 vs 3.1 months compared to letrozole alone. A separate phase 2 study combining fulvestrant with abemaciclib showed a 44% overall response rate with responses exclusively in G1 and G2 endometrioid tumors classified as NSMP by TCGA.
These findings demonstrate that subsets of heavily pretreated pMMR patients, particularly those with G1 and G2 endometrioid tumors, can respond well to endocrine-based combinations. Phase 3 trials are planned to further define the role of CDK inhibitors combined with hormonal therapy in EC management.
Radiation combined with immunotherapy represents an area of active investigation based on the abscopal effect, where radiation at one site can trigger immune responses against distant tumors. Several phase 1 and 2 trials are evaluating this combination in recurrent and unresectable EC settings, though the KEYNOTE-B21 trial did not show improvement in subgroups receiving radiation.
Primary and secondary resistance to immunotherapy remains a significant challenge. Approximately 25-33% of patients who initially respond to immunotherapy develop secondary resistance through changes in immune signaling pathways, upregulation of alternative inhibitory pathways, and PD-L1 overexpression. Understanding the mechanisms and predictors of resistance is an active research priority.
Treatment sequencing questions are becoming increasingly complex as more agents gain approval. There is currently no data supporting ICI rechallenge after prior immunotherapy in EC, the optimal duration of maintenance immunotherapy is uncertain, and the role of different agents across molecular subgroups in various lines of therapy requires further investigation through prospective clinical trials.
The treatment landscape of advanced and recurrent endometrial cancer has been fundamentally transformed by the integration of molecular classification into clinical practice. Immune checkpoint inhibitors combined with chemotherapy are now standard first-line therapy, with treatment algorithms branching based on dMMR vs pMMR status, HER-2 expression, and TP53 mutation status to guide agent selection.
Key advances include FDA approvals for pembrolizumab and dostarlimab with chemotherapy, lenvatinib plus pembrolizumab for recurrent pMMR disease, and trastuzumab deruxtecan for HER2-positive tumors. The RAINBO trial represents the next frontier, prospectively enrolling patients into four molecular subgroup-specific treatment cohorts to validate the paradigm of molecularly guided therapy.
Significant challenges remain, including the high cost of novel therapeutics exceeding $200,000 per year, limited global access to molecular testing and new drugs, and the need to better characterize the heterogeneous pMMR population which likely contains distinct molecular subsets requiring different treatment strategies. Continued research is essential to optimize treatment for all EC patients.