The RUBY and NRG-GY018 trials are the headline story: both established checkpoint inhibitor plus chemotherapy combinations as the new first-line standard for advanced endometrial cancer in 2022–2023, with the benefit most dramatic in dMMR/MSI-H tumors — where 3-year PFS nearly quadrupled in some analyses. But the field can't stop there. MSI-H tumors represent about 30% of endometrial cancers. The remaining 70% — particularly p53-mutant serous histology and NSMP tumors — still have limited options after platinum-based chemotherapy. The 2026 trial agenda is squarely focused on those populations: HER2-directed ADCs, FRα-targeting mirvetuximab, and POLE de-escalation approaches that could spare some patients from chemotherapy entirely.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Quick Summary
Endometrial cancer trials in 2026 are stratified by molecular subtype: POLE-mutant (best prognosis, immunotherapy trials), dMMR/MSI-H (~30%, pembrolizumab/dostarlimab now standard), p53-mutant (worst prognosis, ADC trials), and NSMP/pMMR. Key approved combinations: dostarlimab+carboplatin/paclitaxel (RUBY), pembrolizumab+chemotherapy (NRG-GY018), lenvatinib+pembrolizumab (second-line). New 2026 trials: HER2-directed ADCs, FRα-targeting mirvetuximab, and PARP inhibitors for BRCA-mutant uterine cancer.
ClinicalMetric Analysis
- Molecular subtype testing (POLE, MMR/MSI, p53, NSMP) is now clinically mandatory for advanced endometrial cancer — it directly determines immunotherapy eligibility that affects survival, and patients who haven't had it done are missing treatment-determining information. Patients with advanced endometrial cancer who have only had histological typing (endometrioid, serous, clear cell) without molecular characterization are missing the stratification data that determines whether pembrolizumab or dostarlimab adds meaningful survival benefit. dMMR/MSI-H patients — about 30% of endometrial cancers — have demonstrated hazard ratios below 0.5 for PFS with immunotherapy addition in RUBY and NRG-GY018. For POLE-mutant patients (5–10%), the biology is so immunogenically active that trials are now asking whether immunotherapy is adequate without chemotherapy. Requesting molecular profiling at diagnosis, not at recurrence, is the clinical timing that preserves the most treatment options.
- POLE-mutant tumors have such an exceptionally favorable prognosis that de-escalation trials are actively testing whether these patients can safely receive less chemotherapy — an unusual research hypothesis where less treatment may be the optimal approach. POLE-mutant endometrial cancers have 5-year OS rates exceeding 90% even in high-grade histology, because the hypermutation that POLE exonuclease dysfunction creates generates abundant neoantigens that make these tumors extremely immunogenic. ESMO and GOG-coordinated trials are now testing whether POLE-mutant patients with stage III/IV disease can achieve equivalent outcomes with immunotherapy alone (avoiding chemotherapy toxicity) or with reduced chemotherapy dose intensity. This is a trial design hypothesis that runs counter to oncology's historical instinct toward dose intensification — and it has direct implications for a subgroup of patients who have historically received full-intensity treatment they may not have needed.
- RUBY and NRG-GY018 converged on the same clinical conclusion from different trial designs: immunotherapy + chemotherapy is the new first-line standard for advanced/recurrent endometrial cancer across molecular subtypes — but the benefit is 3–4x larger in dMMR/MSI-H disease, and patients need this distinction to understand their prognosis. Cross-trial comparison is unreliable, but the directional consistency across RUBY (dostarlimab) and NRG-GY018 (pembrolizumab) in showing benefit regardless of MMR status — while the dMMR/MSI-H subgroup drives the largest absolute gains — allows oncologists to recommend immunotherapy addition for all comers without waiting for subtype results. The practical implication: patients with newly diagnosed advanced endometrial cancer should expect a checkpoint inhibitor to be part of their first-line regimen in 2026, while simultaneously proceeding with molecular profiling to understand their specific prognosis and eligibility for the next tier of biomarker-selected trials.
The Molecular Classification That Drives Trial Eligibility
The 2020 WHO classification divides endometrial cancer into four molecular subtypes — each with distinct biology, prognosis, and treatment implications. Knowing your molecular subtype is now the starting point for any conversation about advanced therapy or clinical trial eligibility:
| Subtype | Frequency | Key Treatments/Trials |
|---|---|---|
| POLE-mutant | ~7–10% | Immunotherapy alone (PORTEC-4a), excellent prognosis |
| dMMR/MSI-H | ~25–30% | Pembrolizumab, dostarlimab (approved 1L); neoantigen vaccine trials |
| p53-mutant | ~20–25% | T-DXd (HER2+), ADC trials, PARP inhibitors (BRCA co-mutation) |
| NSMP (no specific molecular profile) | ~40% | Lenvatinib+pembrolizumab (2L); hormone therapy (ER+); FRα trials |
The RUBY and NRG-GY018 Results: What They Changed
These two trials transformed first-line treatment for advanced endometrial cancer within the same 18-month window, and their results are worth understanding in quantitative terms rather than summary language.
RUBY trial (dostarlimab + carboplatin/paclitaxel)
In the dMMR/MSI-H population — approximately 30% of enrolled patients — 3-year progression-free survival was 61.4% in the dostarlimab arm versus 15.7% for placebo plus chemotherapy. Not a modest improvement; a near-fourfold difference in the proportion of patients progression-free at three years. In the overall enrolled population (regardless of MMR status), 2-year overall survival was 71.3% versus 56.0%. Dostarlimab (Jemperli, GSK) plus chemotherapy received FDA and EMA approval as first-line advanced endometrial cancer treatment in 2023–2024.
NRG-GY018 (pembrolizumab + carboplatin/paclitaxel)
Parallel results from the NRG Oncology cooperative group. In dMMR/MSI-H patients, pembrolizumab plus chemotherapy reduced the hazard of progression or death by 70% (HR 0.30) versus placebo plus chemotherapy. In pMMR patients — the majority — 12-month PFS was 54% versus 38%, a more modest but real benefit that supports pembrolizumab use across all MMR strata. Both regimens are now considered standard of care; the choice between them depends on institution preference, cost, and guideline recommendations in a given country.
Key Trials Recruiting in 2026
Trastuzumab Deruxtecan (T-DXd) for HER2-Positive Endometrial Cancer
HER2 amplification or overexpression occurs in approximately 30% of uterine serous carcinomas — the p53-mutant, high-grade histology with the worst prognosis in endometrial cancer and limited benefit from checkpoint inhibitors. Trastuzumab deruxtecan (T-DXd, Enhertu, AstraZeneca/Daiichi Sankyo) is an antibody-drug conjugate — trastuzumab linked to a potent topoisomerase I inhibitor payload, with high membrane permeability that also kills bystander tumor cells without HER2 expression. Its activity across HER2-positive solid tumors has been transformative.
DESTINY-PanTumor02 reported an overall response rate of 57.5% in HER2-positive endometrial cancer (IHC 3+ or IHC 2+/ISH+). DESTINY-Endometrial01 and related trials are now studying T-DXd in earlier settings and in combination with pembrolizumab for HER2-positive disease. Eligibility typically requires: HER2 IHC 3+ or 2+ confirmed by central testing, prior platinum-containing therapy, no prior HER2-directed therapy. HER2 testing should be performed with guidelines-concordant methodology — a non-trivial consideration given that endometrial cancer HER2 scoring uses gynecologic oncology-specific criteria distinct from breast cancer HER2 testing criteria.
Mirvetuximab Soravtansine for FRα-Expressing Endometrial Cancer
Mirvetuximab soravtansine (ELAHERE, ImmunoGen) targets folate receptor alpha (FRα) — a surface protein expressed in many gynecologic malignancies. Following its accelerated approval in ovarian cancer based on FORWARD-I trial data, mirvetuximab is being evaluated in FRα-positive endometrial cancer in the FRANOVA-endo trial. The trial is enrolling patients with high FRα expression (at least 75% of cells staining 2+ or 3+ by immunohistochemistry) who have progressed on at least one prior systemic therapy. FRα expression testing is required upfront and needs to be performed using the VENTANA FOLR1 assay in a certified laboratory — not all pathology departments have this test available, and patients may need to send tissue to a reference lab.
PORTEC-4a: De-escalation in POLE-Mutant Disease
PORTEC-4a (NCT03469674) is a de-escalation trial — one of the most important design concepts in cancer research, and all too rare. POLE-mutant endometrial cancers have an ultramutated genome that generates thousands of neoantigens, making them exquisitely immunogenic. Despite their high mutational burden, they carry the best prognosis of any endometrial cancer molecular subtype, and the question being asked here is whether adjuvant chemotherapy and radiotherapy — which these patients currently receive per standard guidelines — are doing more harm than good. PORTEC-4a randomizes POLE-mutant stage I–II patients post-surgery to adjuvant radiotherapy, observation, or single-agent immunotherapy. POLE mutation confirmation by NGS is required, and critically, not all NGS panels cover the relevant exonuclease domain hotspot codons — patients should verify their panel covers positions 286, 411, 413, 444, 456, and 459.
Uterine Sarcoma: A Distinct Landscape
Uterine leiomyosarcoma is biologically and clinically distinct from endometrial carcinoma and is excluded from most endometrial carcinoma trials. The uterine LMS trial landscape in 2026 includes: eribulin versus paclitaxel (Phase 3) for second-line uterine LMS, trabectedin maintenance for disease stabilized on first-line therapy, and tazemetostat for EZH2-mutant uterine sarcoma (an emerging subgroup defined by EZH2 loss-of-function mutations). Carcinosarcoma (malignant mixed Müllerian tumor) — historically grouped with sarcoma but increasingly understood as metaplastic carcinoma — has specific pembrolizumab combination trials given its ~20% MMR-deficient rate and high microsatellite instability frequency.
Getting Molecular Testing Right Before Searching for Trials
Molecular profiling is now the prerequisite, not the optional add-on, for endometrial cancer trial access. What to request specifically:
- MMR/MSI testing: IHC for MLH1, MSH2, MSH6, PMS2 — loss of any protein defines dMMR. PCR or NGS-based MSI testing is confirmatory. Required for checkpoint inhibitor eligibility and determines the magnitude of benefit.
- POLE sequencing: NGS panel including POLE exonuclease domain mutations at hotspot codons 286, 411, 413, 444, 456, 459. Standard oncology panels may not cover all of these — confirm with the testing laboratory before assuming a negative result is definitive.
- HER2 IHC/ISH: Essential for serous histology (p53-mutant subtype). Gynecologic oncology scoring criteria differ from breast cancer criteria. Required for T-DXd and related HER2-directed ADC trials.
- TP53 sequencing: Identifies the p53-mutant subtype — the highest-risk group with greatest need for novel therapies.
- FRα IHC: Required for mirvetuximab trials. Must use VENTANA FOLR1 assay with the high-expression scoring criterion (≥75% cells 2+ or 3+).
- BRCA1/2 germline and somatic testing: A minority of endometrial cancers carry BRCA mutations; these patients may be eligible for PARP inhibitor trials. Germline testing also has family implications.
Find Uterine Cancer Trials
Search recruiting endometrial and uterine cancer trials by molecular subtype, phase, treatment type, and location.
Frequently Asked Questions
What uterine cancer treatments are in clinical trials in 2026?
2026 active trials: immunotherapy combinations (pembrolizumab + lenvatinib is now standard; trials adding PARP inhibitors or ADCs); HER2-targeted ADCs (trastuzumab deruxtecan for HER2+ endometrial cancer); PI3K/AKT/mTOR pathway inhibitors; FGFR inhibitors for FGFR-mutant tumors; and uterine sarcoma-specific trials.
Should I get molecular testing before joining a uterine cancer trial?
Yes — molecular profiling is essential. Key markers: MMR/MSI status (immunotherapy eligibility), POLE mutation (ultra-good prognosis), HER2 amplification (HER2-targeted therapy eligible), FGFR2 mutations, and PIK3CA mutations. Ask your oncologist for comprehensive genomic profiling before choosing a trial.
Is immunotherapy effective for endometrial cancer?
Yes — especially in MMR-deficient (dMMR) or MSI-H tumors. Pembrolizumab + lenvatinib is now FDA-approved for advanced endometrial cancer regardless of MSI status. Dostarlimab is approved for dMMR endometrial cancer. Ongoing trials test whether immunotherapy can replace or reduce chemotherapy in early-stage high-risk disease.