{"entity":{"id":"enthuse-m1-zibotentan","kind":"trial","name":"ENTHUSE M1","aka":["ENTHUSE M1","ENTHUSE 14","ZD4054 in bone-metastatic CRPC"],"tldr":"A drug blocking the endothelin signal that prostate cancer uses in bone did not extend life, and it caused swelling, headaches and heart failure.","summary":"ENTHUSE M1 randomised 594 men with castration-resistant prostate cancer and bone metastases, pain-free or mildly symptomatic, 1:1 to zibotentan 10 mg daily or placebo added to standard treatment.\n\nMedian overall survival was 24.5 months with zibotentan and 22.5 months with placebo, hazard ratio 0.87 (95.2 percent confidence interval 0.69 to 1.10, p=0.240). No statistically significant difference was observed for any secondary efficacy endpoint, which included time to pain progression, time to chemotherapy, and time to new bone metastases.\n\nPeripheral oedema (44 percent) and headache (31 percent) were the commonest adverse events with zibotentan, both direct consequences of endothelin A blockade. Cardiac failure of any grade occurred in 5.7 percent against 1.7 percent, and of grade 3 or worse in 3.0 against 1.0 percent, described as manageable and reversible.\n\nThe other two ENTHUSE trials, zibotentan with docetaxel and zibotentan in non-metastatic disease, were also negative, and AstraZeneca discontinued the programme in prostate cancer.","status":"negative","asOf":"2026-09-25","links":[{"label":"ClinicalTrials.gov NCT00554229","url":"https://clinicaltrials.gov/study/NCT00554229"},{"label":"ENTHUSE M1 (Cancer 2012)","url":"https://doi.org/10.1002/cncr.27674"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":[],"targets":["ednra"],"drugs":["zibotentan"],"companies":["astrazeneca"],"institutions":[],"pathways":[],"terms":["bone-metastases","castration-resistance"],"trials":["swog-s0421-atrasentan"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT00554229","phase":"3","setting":"Castration-resistant prostate cancer with bone metastases in men who were pain-free or mildly symptomatic: zibotentan 10 mg daily or placebo added to standard prostate cancer treatment, with overall survival as the primary endpoint","sponsor":"AstraZeneca","result":"Median overall survival 24.5 against 22.5 months (hazard ratio 0.87, 95.2 percent confidence interval 0.69 to 1.10, p=0.240): not significant, with peripheral oedema in 44 percent and cardiac failure of any grade in 5.7 against 1.7 percent.","yearReported":2012,"enrolled":594,"enrolledBasis":"randomised","enrolledNote":"594 men were randomised 1:1, 299 to zibotentan and 295 to placebo.","outcomes":[{"endpoint":"Overall survival (median)","primary":true,"unit":"months","arms":[{"name":"Zibotentan 10 mg daily","n":299,"value":24.5,"note":"Confidence interval is 95.2 percent, as reported."},{"name":"Placebo","n":295,"value":22.5}],"hr":0.87,"ci":[0.69,1.1],"p":"0.240","source":"https://doi.org/10.1002/cncr.27674"},{"endpoint":"Cardiac failure, any grade","unit":"%","arms":[{"name":"Zibotentan 10 mg daily","n":299,"value":5.7},{"name":"Placebo","n":295,"value":1.7}],"source":"https://doi.org/10.1002/cncr.27674"}],"replication":"SWOG S0421 found the same for atrasentan with docetaxel in 994 men."},"route":"/trials/enthuse-m1-zibotentan/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"target":[{"id":"ednra","kind":"target","name":"EDNRA","route":"/targets/ednra/"}],"drug":[{"id":"atrasentan","kind":"drug","name":"Atrasentan","route":"/drugs/atrasentan/"},{"id":"zibotentan","kind":"drug","name":"Zibotentan","route":"/drugs/zibotentan/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"}],"term":[{"id":"bone-metastases","kind":"term","name":"Bone metastases and skeletal-related events","route":"/terms/bone-metastases/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"prostate-failed-programmes","kind":"term","name":"Prostate cancer programmes that failed, and what each failure taught","route":"/terms/prostate-failed-programmes/"}],"trial":[{"id":"swog-s0421-atrasentan","kind":"trial","name":"SWOG S0421","route":"/trials/swog-s0421-atrasentan/"}]}}