# Bipolar androgen therapy (BAT)

Source: https://onco.cc/terms/bipolar-androgen-therapy/  
OnCo record `bipolar-androgen-therapy` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Deliberately giving large doses of testosterone to men whose prostate cancer has learned to live without it, swinging the level from very high to very low each month. It is the opposite of standard treatment, and about a third of men respond, with about half then responding again to the hormone-blocking drug that had stopped working.

## Summary

Bipolar androgen therapy is rapid cycling between supraphysiological and near-castrate serum testosterone, achieved by giving intramuscular testosterone cipionate 400 mg every 28 days while continuing luteinising hormone-releasing hormone agonist therapy, so the level peaks far above the normal range and falls back towards castrate before the next dose. The rationale comes directly from the mechanism of castration resistance established by Visakorpi and by Chen: a cell that survives androgen deprivation by amplifying and overexpressing the androgen receptor is, on that account, adapted to a low-ligand environment and vulnerable to a high-ligand one.

The evidence is two trials from Johns Hopkins. RESTORE gave it to 30 asymptomatic men whose metastatic castration-resistant disease had progressed on enzalutamide: 9 of 30 (30 percent; 95 percent confidence interval 15 to 49) had a prostate-specific antigen fall of at least 50 percent, and of the 21 who went on to enzalutamide rechallenge afterwards, 15 (52 percent; 33 to 71) responded again. TRANSFORMER randomised 195 asymptomatic men to bipolar androgen therapy or enzalutamide with crossover allowed at progression. The primary endpoint was flat, 5.7 months in both arms (hazard ratio 1.14; 0.83 to 1.55). The interesting results were secondary: 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; progression-free survival through crossover was 28.2 months for the bipolar-then-enzalutamide sequence against 19.6 months for the reverse (hazard ratio 0.44; 0.22 to 0.88); overall survival did not differ (32.9 against 29.0 months; hazard ratio 0.95); and patient-reported quality of life consistently favoured bipolar androgen therapy.

It is not standard care anywhere and it is not safe in everyone. Both trials excluded men with more than five visceral sites or bone lesions at risk of fracture, because of the risk of tumour flare, and enrolled only asymptomatic men. Cardiovascular and thromboembolic events occurred: hypertension in 3 of 30 in RESTORE, with single grade 3 or worse events including pulmonary embolism, myocardial infarction, urinary obstruction, gallstone and sepsis. The case for a definitive trial rests on the resensitisation effect rather than the direct response rate, and the endpoint that would show it, progression-free survival through the second line, is not the one phase 3 trials usually use.

## Fields

- Kind: Term
- Last checked: 2026-09-25
- Also known as: BAT; bipolar androgen therapy; supraphysiological testosterone; high-dose testosterone therapy; testosterone cycling prostate cancer
- Tags: gu; prostate-glossary

## Notes

- Bipolar androgen therapy is not the same as intermittent androgen deprivation, and confusing the two is the commonest error here. Intermittent deprivation pauses treatment and lets testosterone drift back towards normal, to give the man a break from side effects. Bipolar androgen therapy pushes testosterone far above normal on purpose, while castration continues underneath, to attack a cell that has adapted to its absence. One is a rest; the other is an attack.
- It is testosterone, which men with prostate cancer are taught to fear, and the fear is not unfounded outside the trial population. The trials enrolled asymptomatic men without high-risk sites for tumour flare; a man with spinal disease, extensive visceral metastases or symptoms is exactly the man in whom a testosterone surge is dangerous. This is a trial treatment, and it should be had inside a trial.
- Why the endpoint matters for whether it ever gets licensed. The benefit shows up in what happens after bipolar androgen therapy, as resensitisation to a drug that had failed. A conventional progression-free survival endpoint measures only the first step and was flat in TRANSFORMER. That is the argument for progression-free survival through the second line as the primary endpoint of a phase 3.

## Sources

- Teply et al., Lancet Oncology 2018 (RESTORE): bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer: https://doi.org/10.1016/s1470-2045(17)30906-3
- Denmeade et al., Journal of Clinical Oncology 2021 (TRANSFORMER): bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer: https://doi.org/10.1200/jco.20.02759

## Connected records

- key papers: [Molecular determinants of resistance to antiandrogen therapy](https://onco.cc/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/), [RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/), [TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021/)
- ideas: [Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer](https://onco.cc/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/), [Rotate between drugs on a fixed schedule instead of waiting for failure](https://onco.cc/ideas/idea-bio1-alternating-schedules/), [Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint](https://onco.cc/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/)
- terms: [Androgen deprivation therapy (ADT)](https://onco.cc/terms/adt/), [Androgen deprivation therapy (ADT)](https://onco.cc/terms/androgen-deprivation-therapy/), [AR-V7 splice variant](https://onco.cc/terms/ar-v7/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Intermittent androgen deprivation (IAD)](https://onco.cc/terms/intermittent-androgen-deprivation/), [PSA50 / PSA90 response](https://onco.cc/terms/psa50/), [Quality of life](https://onco.cc/terms/quality-of-life/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- fronts: [Hormonal Therapy](https://onco.cc/fronts/hormonal/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/)
- drugs: [Abiraterone acetate](https://onco.cc/drugs/abiraterone/), [Enzalutamide](https://onco.cc/drugs/enzalutamide/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [No incentive to repurpose cheap drugs](https://onco.cc/bottlenecks/b-generic-repurposing/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)

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