A new clinical trial will test whether hormone tablets can replace chemotherapy for women with a common type of endometrial cancer, sparing them severe side effects. Endometrial cancer is the most frequent gynaecological cancer, and current treatment decisions rely on imprecise clinical features. Doctors must balance the risk of recurrence against toxic chemotherapy. A recent molecular classification splits tumours into four groups, each with different outcomes. For the largest group—no specific molecular profile (NSMP)—it is unclear whether chemoradiotherapy helps. The NSMP-ORANGE trial will recruit 600 women with hormone-sensitive NSMP tumours across the UK, Netherlands, France, and Canada. Half will receive standard chemoradiotherapy; the other half will get radiotherapy followed by two years of daily progestin tablets. The trial will measure whether the hormone-only approach is as effective at preventing recurrence while reducing toxicity and improving quality of life. If successful, this trial could replace chemotherapy with a well-tolerated oral hormone treatment for thousands of women each year. The results will feed into the wider RAINBO programme, which aims to personalise adjuvant therapy for all four molecular subtypes of high-risk endometrial cancer, redefining clinical practice globally.
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BACKGROUND Endometrial cancer is the most common gynaecological cancer. The cornerstone of treatment is surgery with adjuvant therapy for women at increased risk of recurrence based on clinico-pathological features. This is imprecise and clinicians and patients must balance the risks of poor survival outcomes with treatment-related toxicity. A new molecular classification system identifies four groups with different prognostic profiles: p53-abnormal (p53abn), POLE-mutant (POLEmut), mismatch repair-deficient (MMRd) and no specific molecular profile (NSMP). The PORTEC-3 trial showed that adjuvant chemoradiotherapy is beneficial for high-risk endometrial cancer patients overall but when stratified by molecular group, only p53abn tumours showed a clear benefit, POLEmut and MMRd tumours showed no benefit, and the benefit for NSMP tumours was uncertain. RESEARCH QUESTION Refining Adjuvant treatment IN endometrial cancer Based On molecular profile (RAINBO) is a collaborative international umbrella programme of four adjuvant treatment trials in high-risk endometrial cancer. It asks whether personalised treatment based on molecular group reduces cancer recurrence whilst minimising harms from unnecessary chemotherapy. Here we seek support for UK recruitment to the NSMP-ORANGE trial, which will test the effectiveness of adjuvant progestin therapy in hormone-sensitive NSMP tumours. AIMS NSMP-ORANGE aims to investigate whether adjuvant radiotherapy with maintenance progestin tablets is as effective as chemoradiotherapy, whilst reducing toxicity and thus improving quality of life, in patients with high-risk NSMP endometrial cancer. METHODS NSMP-ORANGE is an international, multicentre, randomised phase III non-inferiority trial coordinated by the CRUK and UCL Cancer Trials Centre. Molecular profiling will use immunohistochemistry (p53, MMR and estrogen receptor (ER) expression) and POLE next generation sequencing on diagnostic biopsies. Eligible women will have completely resected stage II with substantial lymphovascular space invasion or stage III ER+ NSMP tumours. Participants will be randomised 1:1 to chemoradiotherapy (standard care) or radiotherapy followed by 2 years of oral progestin. Follow up (to 5 years) will record survival events, toxicity and quality of life in a uniform manner to enable pooling for the overarching RAINBO programme. Assuming a 3-year recurrence-free survival (RFS) rate of 82.5%, a non-inferiority margin of 7.5% will exclude a RFS rate below 75%. 600 patients, recruited over 5 years with 3 years of additional follow-up, are required to observe 153 events, for 80% power at the one-sided 5% significance level after allowing for 5% dropout. Approximately 300 UK patients will be recruited from 25-30 participating centres and 300 from international sites (funded separately), including the Netherlands, France and Canada, who are leading the MMRd-GREEN, p53abn-RED and POLEmut-BLUE RAINBO trials respectively. Clinically-annotated tumour blocks will be prospectively collected and biobanked in Leiden for trial-specific and overarching translational research programmes. TIMELINES One year to set up and obtain approvals; five years to recruit; three years follow up; and one year to analyse and publish our findings. NSMP-ORANGE will take 10 years to complete. ANTICIPATED IMPACT NSMP-ORANGE and the wider RAINBO programme will redefine clinical practice by personalising treatment for women with high-risk endometrial cancer.
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