{"entity":{"id":"keynote-991","kind":"trial","name":"KEYNOTE-991","aka":["KEYNOTE-991","MK-3475-991"],"tldr":"The last attempt to make immunotherapy work in prostate cancer, this time as early as possible. It was stopped for futility and made rashes and serious side effects much commoner.","summary":"KEYNOTE-991 tested whether checkpoint blockade would work if given early, before castration resistance, when the tumour is less heavily pretreated. It randomised 1,251 men with metastatic hormone-sensitive prostate cancer who had not had a next-generation hormonal agent to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles, with enzalutamide 160 mg daily and continuous androgen deprivation.\n\nAt the first interim analysis, median follow-up 21.1 months, radiographic progression-free survival was not superior with pembrolizumab: median not reached in either arm, hazard ratio 1.20 (95 percent confidence interval 0.96 to 1.49, p=0.9467). Median overall survival was not reached in either arm, hazard ratio 1.16 (0.88 to 1.53), not formally tested under the multiplicity strategy. The trial did not meet its primary endpoint and was stopped for futility.\n\nGrade 3 or higher adverse events occurred in 61.9 percent with pembrolizumab against 38.1 percent with placebo, and serious adverse events in 40.3 against 23.2 percent. Rash of any grade occurred in 25.1 against 9.3 percent, identified as an additional safety signal for the combination.\n\nWith IMbassador250, KEYNOTE-641 and KEYNOTE-921, this closes the unselected checkpoint inhibitor question in prostate cancer. The remaining immunotherapy indication is pembrolizumab for the roughly 3 percent of men with mismatch repair deficient or microsatellite instability high tumours, where selection does the work.","status":"negative","asOf":"2026-09-25","links":[{"label":"ClinicalTrials.gov NCT04191096","url":"https://clinicaltrials.gov/study/NCT04191096"},{"label":"KEYNOTE-991 (Annals of Oncology 2025)","url":"https://doi.org/10.1016/j.annonc.2025.05.008"}],"tags":[],"related":[],"cancers":["prostate","prostate-mhspc"],"sections":[],"technologies":["checkpoint-inhibitor","androgen-deprivation"],"targets":["pd1","androgen-receptor"],"drugs":["pembrolizumab","enzalutamide"],"companies":["merck"],"institutions":[],"pathways":[],"terms":["mcrpc-mhspc","arpi","adt"],"trials":["keynote-641","keynote-921","imbassador250","arches","enzamet"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT04191096","phase":"3","setting":"Metastatic hormone-sensitive prostate cancer not previously treated with a next-generation hormonal agent: pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles with enzalutamide 160 mg daily and continuous androgen deprivation, with primary endpoints of radiographic progression-free survival and overall survival","sponsor":"Merck Sharp & Dohme","result":"Radiographic progression-free survival hazard ratio 1.20 (95 percent confidence interval 0.96 to 1.49, p=0.9467), medians not reached; stopped for futility. Grade 3 or higher adverse events 61.9 against 38.1 percent and rash 25.1 against 9.3 percent.","yearReported":2025,"enrolled":1251,"enrolledBasis":"randomised","enrolledNote":"1,251 participants were randomly assigned between 2 March 2020 and 9 August 2021, 626 to pembrolizumab and 625 to placebo.","outcomes":[{"endpoint":"Radiographic progression-free survival","primary":true,"arms":[{"name":"Pembrolizumab with enzalutamide and androgen deprivation","n":626,"note":"median not reached"},{"name":"Placebo with enzalutamide and androgen deprivation","n":625,"note":"median not reached"}],"hr":1.2,"ci":[0.96,1.49],"p":"0.9467","source":"https://doi.org/10.1016/j.annonc.2025.05.008"},{"endpoint":"Grade 3 or higher adverse events","unit":"%","arms":[{"name":"Pembrolizumab with enzalutamide and androgen deprivation","n":626,"value":61.9},{"name":"Placebo with enzalutamide and androgen deprivation","n":625,"value":38.1}],"source":"https://doi.org/10.1016/j.annonc.2025.05.008"}],"replication":"Consistent with IMbassador250, KEYNOTE-641 and KEYNOTE-921 in castration-resistant disease; the failure is now shown at both ends of the disease course."},"route":"/trials/keynote-991/","neighbours":{"cancer":[{"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":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"term":[{"id":"adt","kind":"term","name":"Androgen deprivation therapy (ADT)","route":"/terms/adt/"},{"id":"arpi","kind":"term","name":"Androgen receptor pathway inhibitor (ARPI)","route":"/terms/arpi/"},{"id":"mcrpc-mhspc","kind":"term","name":"mCRPC and mHSPC (castration-resistant vs hormone-sensitive prostate cancer)","route":"/terms/mcrpc-mhspc/"},{"id":"prostate-failed-programmes","kind":"term","name":"Prostate cancer programmes that failed, and what each failure taught","route":"/terms/prostate-failed-programmes/"}],"trial":[{"id":"arches","kind":"trial","name":"ARCHES","route":"/trials/arches/"},{"id":"enzamet","kind":"trial","name":"ENZAMET","route":"/trials/enzamet/"},{"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/"}]}}