{"entity":{"id":"ca184-043-ipilimumab","kind":"trial","name":"CA184-043","aka":["CA184-043","ipilimumab after radiotherapy in mCRPC"],"tldr":"The first big immunotherapy trial in prostate cancer. It missed by a hair, and the way it missed, harm early and benefit late, was the clue nobody managed to cash in.","summary":"CA184-043 randomised 799 men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel to a single 8 Gy fraction of bone-directed radiotherapy followed by ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses, with maintenance every 3 months for non-progressors.\n\nMedian overall survival was 11.2 months (95 percent confidence interval 9.5 to 12.7) with ipilimumab and 10.0 months (8.3 to 11.0) with placebo, hazard ratio 0.85 (0.72 to 1.00, p=0.053). It missed significance, and the proportional hazards assumption was violated (p=0.0031), which is the interesting part. A piecewise hazard model showed the hazard ratio changed with time: 1.46 (1.10 to 1.95) in the first 5 months, 0.65 (0.50 to 0.85) from 5 to 12 months and 0.60 (0.43 to 0.86) beyond 12 months. Ipilimumab appeared to kill men early and help those who survived the early period.\n\nThe toxicity explains the first phase. Grade 3 to 4 immune-related adverse events occurred in 101 of 393 men (26 percent) against 11 of 396 (3 percent), including diarrhoea in 64 (16 percent) against seven (2 percent) and colitis in 18 (5 percent) against none. Four deaths were attributed to study drug toxicity, all with ipilimumab.\n\nThe companion trial CA184-095, in chemotherapy-naive men without visceral metastases, also failed to improve overall survival. No prospectively defined subgroup was ever found in which ipilimumab helps men with prostate cancer.","status":"negative","asOf":"2026-09-25","links":[{"label":"ClinicalTrials.gov NCT00861614","url":"https://clinicaltrials.gov/study/NCT00861614"},{"label":"CA184-043 (Lancet Oncology 2014)","url":"https://doi.org/10.1016/S1470-2045(14)70189-5"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["ctla4"],"drugs":["ipilimumab"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["castration-resistance","bone-metastases"],"trials":["imbassador250","impact-sipuleucel-t","keynote-921"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT00861614","phase":"3","setting":"Metastatic castration-resistant prostate cancer with at least one bone metastasis, progressing after docetaxel: bone-directed radiotherapy of 8 Gy in one fraction followed by ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses, then maintenance every 3 months, with overall survival as the primary endpoint","sponsor":"Bristol-Myers Squibb","result":"Median overall survival 11.2 against 10.0 months (hazard ratio 0.85, 95 percent confidence interval 0.72 to 1.00, p=0.053), missing significance; hazard ratio 1.46 in the first 5 months and 0.60 beyond 12 months. Grade 3 to 4 immune-related adverse events 26 against 3 percent, with four treatment-related deaths.","yearReported":2014,"enrolled":799,"enrolledBasis":"randomised","enrolledNote":"799 men were randomly assigned between 26 May 2009 and 15 February 2012, 399 to ipilimumab and 400 to placebo, and all were included in the intention-to-treat analysis.","outcomes":[{"endpoint":"Overall survival (median)","primary":true,"unit":"months","arms":[{"name":"Ipilimumab 10 mg/kg after 8 Gy radiotherapy","n":399,"value":11.2,"note":"Proportional hazards violated (p=0.0031); piecewise hazard ratio 1.46 at 0 to 5 months, 0.65 at 5 to 12 months, 0.60 beyond 12 months."},{"name":"Placebo after 8 Gy radiotherapy","n":400,"value":10}],"hr":0.85,"ci":[0.72,1],"p":"0.053","source":"https://doi.org/10.1016/S1470-2045(14)70189-5"},{"endpoint":"Grade 3 to 4 immune-related adverse events","unit":"%","arms":[{"name":"Ipilimumab 10 mg/kg after 8 Gy radiotherapy","n":393,"value":26},{"name":"Placebo after 8 Gy radiotherapy","n":396,"value":3}],"source":"https://doi.org/10.1016/S1470-2045(14)70189-5"}],"replication":"CA184-095, in chemotherapy-naive men, also failed; IMbassador250 and the three KEYNOTE trials later failed with PD-1 and PD-L1 blockade."},"route":"/trials/ca184-043-ipilimumab/","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/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"}],"drug":[{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"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":"imbassador250","kind":"trial","name":"IMbassador250","route":"/trials/imbassador250/"},{"id":"impact-sipuleucel-t","kind":"trial","name":"IMPACT (sipuleucel-T)","route":"/trials/impact-sipuleucel-t/"},{"id":"keynote-921","kind":"trial","name":"KEYNOTE-921","route":"/trials/keynote-921/"},{"id":"prospect-prostvac","kind":"trial","name":"PROSPECT","route":"/trials/prospect-prostvac/"}]}}