Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO) - NSMP-ORANGE Trial: Comparing Radiotherapy With Oral Progestin Tablets vs. the Current Standard Care, Radiotherapy and Chemotherapy, in Patients With NSMP Endometrial Cancer

Inclusion Criteria:

1. Written informed consent and consent for data sharing for the overarching RAINBO programme
2. Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of the aforementioned histotypes
3. Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020, adapted from Vermij et al. 2020)
4. Hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
5. No distant metastases as determined by pre-surgical or post-surgical imaging (CT scan of chest, abdomen and pelvis within 8 weeks of randomisation). Whole-body PET-CT scan is acceptable if this is part of standard of care at participating sites
6. Age ≥ 18 years
7. WHO performance status 0 or 1
8. Expected start of adjuvant treatment within 10 weeks after surgery
9. Patients must be accessible for treatment and follow-up
10. Consent for the donation of a tissue block for translational research for the overarching RAINBO programme
11. FIGO (2018) stage II EC with substantial LVSI or stage III NSMP tumours
12. p53 wildtype, MMR proficient EC with no somatic pathogenic POLE variant (i.e. NSMP)
13. ER+ by IHC (10% threshold applied) or Allred score of ≥3
14. Absolute neutrophil count (ANC) ≥1.5 x 109 /l
15. Platelets ≥ 100 x 109 /L
16. Bilirubin ≤ 1.5 x UNL (or ≤ 3 x ULN for cases of known Gilbert's syndrome)
17. AST/ALT ≤ 2.5 x UNL

Exclusion Criteria:

1. Previous malignancy, except for non-melanoma skin cancer, in the past 5 years
2. Prior pelvic radiation
3. Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) within previous 6 months
4. Thromboembolic event, e.g. pulmonary embolism or deep vein thrombosis, within previous 6 months
5. Impaired renal function: ≤50ml/min (EDTA clearance, or measured creatinine clearance) or creatinine clearance ≤60 ml/min (calculated according to Cockcroft gault)
6. Uncontrolled cardiac disease (defined as cardiac function which would preclude hydration during cisplatin administration and any contraindication to paclitaxel)
7. Peripheral neuropathy, ≥ grade 2
8. Inflammatory bowel disease
9. Known history of porphyria
10. History of active immune deficiency syndromes or uncontrolled HIV infection: HIV positive patients receiving effective antiretroviral therapy and CD4 count \>200 may be included
11. Patients who have received a live attenuated vaccine within 2 weeks prior to planned treatment start
12. Any other condition which as per section 4.3 of the relevant SmPC or in the opinion of the investigator contraindicates the use of chemotherapy, radiotherapy and/or oral progestin tablets
13. The patient is currently participating in another interventional clinical trial or has received an investigational drug (either approved or not approved) in any prior clinical study within 5 half-lives prior to screening