Pragmatic Clinical Trial Resources-Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial progra

Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial progra

Pdf Summary

The RAINBO (Refining Adjuvant treatment IN endometrial cancer Based On molecular features) program is an international platform of four clinical trials designed to personalize adjuvant treatment for endometrial cancer according to the 2020 WHO molecular classification. Endometrial cancer is divided into four molecular subtypes with distinct prognoses: POLE-mutated (POLEmut; excellent outcomes), mismatch repair–deficient (MMRd; intermediate prognosis and immunogenic), p53-abnormal (p53abn; poor prognosis, genomically unstable), and no specific molecular profile (NSMP; heterogeneous, stage/grade dependent). Although molecular classification is now incorporated into European guidelines, important unmet needs remain: some subgroups have high recurrence risk despite current therapy, standard chemoradiation causes substantial long-term toxicity, and evidence is limited for rarer subgroups.

RAINBO evaluates molecular-class–directed strategies after hysterectomy and bilateral salpingo-oophorectomy with no macroscopic residual disease and no distant metastases. Three trials use 3-year recurrence-free survival as the primary endpoint; the POLEmut trial uses 3-year pelvic recurrence.

1) <strong>p53abn-RED (phase III, n=554):</strong> tests whether adding 2 years of the PARP inhibitor olaparib after standard chemoradiation improves outcomes versus chemoradiation alone, based on frequent homologous recombination deficiency in p53abn tumors.

2) <strong>MMRd-GREEN (phase III, n=316):</strong> compares radiotherapy plus concurrent/adjuvant durvalumab for 1 year versus radiotherapy alone, leveraging sensitivity of MMRd cancers to immune checkpoint blockade.

3) <strong>NSMP-ORANGE (phase III non-inferiority, n=600):</strong> a de-escalation approach for estrogen receptor–positive NSMP stage II (with LVSI) or stage III disease, comparing radiotherapy followed by 2 years of progestin to standard chemoradiation to reduce toxicity while maintaining efficacy.

4) <strong>POLEmut-BLUE (phase II, n=145):</strong> evaluates safety of omitting or minimizing adjuvant therapy given consistently excellent POLEmut prognosis.

A central biobank and harmonized data collection enable pooled translational research (~1600 patients total), assessing efficacy, toxicity, quality of life, and cost-utility, with results expected around 2028.

Keywords

RAINBO program

endometrial cancer

molecular classification 2020 WHO

POLE-mutated subtype

mismatch repair–deficient (MMRd)

p53-abnormal (p53abn)

no specific molecular profile (NSMP)

adjuvant therapy personalization

olaparib PARP inhibitor trial

durvalumab immunotherapy trial