{"entity":{"id":"paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021","kind":"paper","name":"TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer","aka":["TRANSFORMER","Denmeade 2021 bipolar androgen therapy randomised"],"tldr":"A randomised comparison of high-dose testosterone against a standard hormone-blocking drug. Neither delayed progression better than the other, but men who had the testosterone first and the drug second lived nearly nine months longer before their second progression, and felt better throughout.","summary":"Samuel Denmeade and colleagues randomised 195 asymptomatic men with castration-resistant metastatic prostate cancer to monthly bipolar androgen therapy (94) or enzalutamide (101), with crossover permitted at progression. The primary endpoint was clinical or radiographic progression-free survival; the secondary endpoints included progression-free survival from randomisation through crossover, which the authors call PFS2.\n\nOn the primary endpoint the trial is flat: 5.7 months in both arms. The interesting result is the sequence effect. Prostate-specific antigen progression-free survival on enzalutamide was 3.8 months when it followed abiraterone and 10.9 months when it followed bipolar androgen therapy, and PFS2 was 28.2 months for the bipolar-then-enzalutamide sequence against 19.6 months for the reverse. Quality of life consistently favoured bipolar androgen therapy. The trial is the reason the approach is worth a phase 3, and PFS2 is the endpoint that phase 3 would need.","asOf":"2026-09-25","links":[{"label":"J Clin Oncol 2021","url":"https://doi.org/10.1200/jco.20.02759"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33617303/"},{"label":"ClinicalTrials.gov NCT02286921","url":"https://clinicaltrials.gov/study/NCT02286921"}],"tags":["prostate-evidence"],"related":["paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013","idea-tr1-adaptive-therapy-randomised-phase-2","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["hormonal"],"technologies":[],"targets":["androgen-receptor"],"drugs":["enzalutamide","abiraterone"],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["castration-resistance","psa","quality-of-life","bipolar-androgen-therapy","radiographic-progression-free-survival"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-trial-design","b-toxicity-qol"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2021,"doi":"10.1200/jco.20.02759","pmid":"33617303","authors":"Denmeade SR, Wang H, Agarwal N, et al.","paperType":"rct","findings":["Progression-free survival 5.7 months in both arms (hazard ratio 1.14; 95 percent confidence interval 0.83 to 1.55; P equals 0.42).","A 50 percent decline in prostate-specific antigen in 28.2 percent on bipolar androgen therapy against 25.3 percent on enzalutamide.","At crossover, a 50 percent prostate-specific antigen decline occurred in 77.8 percent of patients crossing to enzalutamide and 23.4 percent of those crossing to bipolar androgen therapy.","Prostate-specific antigen progression-free survival on enzalutamide was 3.8 months when given after abiraterone and 10.9 months when given after bipolar androgen therapy.","Progression-free survival through crossover was 28.2 months for bipolar androgen therapy followed by enzalutamide against 19.6 months for the reverse sequence (hazard ratio 0.44; 0.22 to 0.88; P equals 0.02); overall survival 32.9 against 29.0 months (hazard ratio 0.95; P equals 0.80). Adverse events on bipolar androgen therapy were primarily grade 1 to 2 and patient-reported quality of life consistently favoured it."],"whatItMeans":"The first randomised evidence that the order in which prostate cancer treatments are given changes how long they work, independently of which treatments they are. It is also a rare trial in which quality of life pointed one way and the primary endpoint pointed nowhere.","caveats":["The primary endpoint was negative; PFS2 and the resensitisation effect are secondary and hypothesis-generating.","195 patients, asymptomatic and without high-risk sites for tumour flare, so the population is selected.","Overall survival did not differ significantly (32.9 against 29.0 months, P equals 0.80), and the crossover design makes survival hard to interpret."],"changedPractice":false,"participants":195},"route":"/key-papers/paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021/","neighbours":{"paper":[{"id":"paper-zhang-nat-commun","kind":"paper","name":"Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer","route":"/key-papers/paper-zhang-nat-commun/"},{"id":"paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","kind":"paper","name":"RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/"},{"id":"paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013","kind":"paper","name":"SWOG 9346: intermittent versus continuous androgen deprivation in metastatic prostate cancer","route":"/key-papers/paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013/"}],"idea":[{"id":"idea-tr1-adaptive-therapy-randomised-phase-2","kind":"idea","name":"Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials","route":"/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/"},{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/"},{"id":"idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","kind":"idea","name":"Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint","route":"/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"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/"}],"section":[{"id":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}],"institution":[{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"}],"term":[{"id":"bipolar-androgen-therapy","kind":"term","name":"Bipolar androgen therapy (BAT)","route":"/terms/bipolar-androgen-therapy/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"psa","kind":"term","name":"PSA (prostate-specific antigen)","route":"/terms/psa/"},{"id":"quality-of-life","kind":"term","name":"Quality of life","route":"/terms/quality-of-life/"},{"id":"radiographic-progression-free-survival","kind":"term","name":"Radiographic progression-free survival (rPFS)","route":"/terms/radiographic-progression-free-survival/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}]}}