{"entity":{"id":"prostate-failed-programmes","kind":"term","name":"Prostate cancer programmes that failed, and what each failure taught","aka":["prostate cancer drug failures","negative prostate trials","prostate cancer graveyard"],"tldr":"More large prostate cancer trials have failed than succeeded. The failures cluster: immunotherapy in unselected men, drugs aimed at blood vessels, drugs aimed at bone signalling, and drugs that improved scans without extending life.","summary":"Seventeen randomised phase 3 trials recorded here did not work. Grouping them shows four distinct lessons.\n\nImmunotherapy in unselected men. IMbassador250 (759 men, atezolizumab with enzalutamide, hazard ratio 1.12), KEYNOTE-641 (1,244 men, pembrolizumab with enzalutamide, 1.04, stopped for futility), KEYNOTE-921 (1,030 men, pembrolizumab with docetaxel, 0.92), KEYNOTE-991 (1,251 men, pembrolizumab with enzalutamide and androgen deprivation in hormone-sensitive disease, radiographic progression-free survival hazard ratio 1.20, stopped for futility) and CA184-043 (799 men, ipilimumab, 0.85, p=0.053). IMbassador250's translational work explains the pattern: prostate tumours express little PD-L1, carry few mutations and admit few T cells, and that does not change as the disease becomes castration-resistant. The exception that proves the rule is pembrolizumab in mismatch repair deficient disease, about 3 percent of men, where selection does the work. PROSTVAC (PROSPECT, 1,297 men) and sipuleucel-T after it show the same for vaccines: only the selected or the lucky benefit, and sipuleucel-T's guidance in England is withdrawn because the marketing authorisation was.\n\nThe tumour microenvironment. Anti-angiogenics: CALGB 90401 with bevacizumab (1,050 men, hazard ratio 0.91, with treatment-related deaths 4.0 against 1.2 percent) and COMET-1 with cabozantinib (1,028 men, 0.90). Endothelin A antagonists: SWOG S0421 with atrasentan (994 men, 1.04, halted for futility) and ENTHUSE M1 with zibotentan (594 men, 0.87). Src inhibition: READY with dasatinib (1,522 men, 0.99). Immunomodulation of the stroma: 10TASQ10 with tasquinimod (1,245 men, overall survival hazard ratio 1.10 despite radiographic progression-free survival 0.64). Five distinct mechanisms, six trials, more than 6,400 men, no survival benefit.\n\nEndpoints that lied. Orteronel in ELM-PC 4 improved median radiographic progression-free survival from 8.7 to 13.8 months, hazard ratio 0.71, and did nothing to overall survival, 0.92. Tasquinimod improved it from 4.4 to 7.0 months, 0.64, with overall survival 1.10, numerically worse. Cabozantinib in COMET-1 produced bone scan responses in 42 against 3 percent of men and radiographic progression-free survival of 5.6 against 2.8 months, and did not extend life. Bevacizumab improved progression-free survival and response rate and quadrupled the treatment-related death rate. In a disease where men live for years after progression, an imaging endpoint is a weak proxy, and these four trials are the reason to say so.\n\nResistance chaperones and splice variants. Custirsen, an antisense oligonucleotide against clusterin, failed in SYNERGY (1,022 men, hazard ratio 0.93) and again in AFFINITY (635 men, 0.95, including in the poor-prognosis subgroup). Galeterone, the only drug taken to phase 3 with a splice-variant selection strategy, could not complete ARMOR3-SV: 953 men were prescreened to find 73 AR-V7 positive, 38 were randomised of a planned 148, and the men who qualified deteriorated before their radiographs were due.\n\nAnd one that did harm. ERA 223 added radium-223 to abiraterone without mandatory bone protection: no benefit on symptomatic skeletal event-free survival (hazard ratio 1.122) and fractures in 29 against 11 percent. PEACE-3 then tested the same idea with enzalutamide and with bone-protecting agents mandatory for everyone and found an overall survival hazard ratio of 0.76. The harm was in the missing supportive drug, not in the radioligand.","status":"established","asOf":"2026-09-25","links":[{"label":"IMbassador250 (Nature Medicine 2022)","url":"https://doi.org/10.1038/s41591-021-01600-6"},{"label":"ELM-PC 4 (Lancet Oncology 2015)","url":"https://doi.org/10.1016/S1470-2045(15)70027-6"},{"label":"COMET-1 (Journal of Clinical Oncology 2016)","url":"https://doi.org/10.1200/JCO.2015.65.5597"},{"label":"ERA 223 (Lancet Oncology 2019)","url":"https://doi.org/10.1016/S1470-2045(18)30860-X"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":[],"technologies":["checkpoint-inhibitor","antiangiogenic","antisense-sirna","targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["castration-resistance","ar-v7"],"trials":["imbassador250","keynote-641","keynote-921","keynote-991","ca184-043-ipilimumab","calgb-90401","comet-1","swog-s0421-atrasentan","enthuse-m1-zibotentan","ready-dasatinib","tasquinimod-10tasq10","elm-pc-4-orteronel","synergy-custirsen","affinity-custirsen","armor3-sv","prospect-prostvac","era-223"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Clinic basics"},"route":"/terms/prostate-failed-programmes/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"antiangiogenic","kind":"technology","name":"Anti-angiogenic therapy","route":"/technologies/antiangiogenic/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"antisense-sirna","kind":"technology","name":"Oligonucleotide therapeutics","route":"/technologies/antisense-sirna/"},{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"}],"term":[{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"}],"trial":[{"id":"tasquinimod-10tasq10","kind":"trial","name":"10TASQ10","route":"/trials/tasquinimod-10tasq10/"},{"id":"affinity-custirsen","kind":"trial","name":"AFFINITY","route":"/trials/affinity-custirsen/"},{"id":"armor3-sv","kind":"trial","name":"ARMOR3-SV","route":"/trials/armor3-sv/"},{"id":"ca184-043-ipilimumab","kind":"trial","name":"CA184-043","route":"/trials/ca184-043-ipilimumab/"},{"id":"calgb-90401","kind":"trial","name":"CALGB 90401","route":"/trials/calgb-90401/"},{"id":"comet-1","kind":"trial","name":"COMET-1","route":"/trials/comet-1/"},{"id":"elm-pc-4-orteronel","kind":"trial","name":"ELM-PC 4","route":"/trials/elm-pc-4-orteronel/"},{"id":"enthuse-m1-zibotentan","kind":"trial","name":"ENTHUSE M1","route":"/trials/enthuse-m1-zibotentan/"},{"id":"era-223","kind":"trial","name":"ERA 223","route":"/trials/era-223/"},{"id":"imbassador250","kind":"trial","name":"IMbassador250","route":"/trials/imbassador250/"},{"id":"keynote-641","kind":"trial","name":"KEYNOTE-641","route":"/trials/keynote-641/"},{"id":"keynote-921","kind":"trial","name":"KEYNOTE-921","route":"/trials/keynote-921/"},{"id":"keynote-991","kind":"trial","name":"KEYNOTE-991","route":"/trials/keynote-991/"},{"id":"prospect-prostvac","kind":"trial","name":"PROSPECT","route":"/trials/prospect-prostvac/"},{"id":"ready-dasatinib","kind":"trial","name":"READY","route":"/trials/ready-dasatinib/"},{"id":"swog-s0421-atrasentan","kind":"trial","name":"SWOG S0421","route":"/trials/swog-s0421-atrasentan/"},{"id":"synergy-custirsen","kind":"trial","name":"SYNERGY","route":"/trials/synergy-custirsen/"}]}}