# RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer

Source: https://onco.cc/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/  
OnCo record `paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Prostate cancer adapts to having almost no testosterone. This trial did the opposite of what the textbook says and gave men large doses of testosterone. Three in ten responded, and more than half responded again to the hormone-blocking drug that had stopped working.

## Summary

Benjamin Teply, Samuel Denmeade and colleagues at Johns Hopkins gave monthly intramuscular testosterone cipionate 400 mg, on top of continued luteinising hormone-releasing hormone agonist therapy, to 30 asymptomatic men whose metastatic castration-resistant prostate cancer had progressed on enzalutamide. Rapid cycling between high and low serum testosterone is called bipolar androgen therapy.

The rationale is the same adaptation described by Visakorpi and Chen. A cell that has upregulated the androgen receptor to survive castration is, on that account, vulnerable to a flood of ligand. The co-primary endpoints were the proportion with a 50 percent fall in prostate-specific antigen on bipolar androgen therapy and on enzalutamide rechallenge afterwards, and both were met. It is the resensitisation result, not the direct response rate, that makes the approach interesting.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Also known as: RESTORE; Teply 2018 bipolar androgen therapy; BAT after enzalutamide
- Tags: prostate-evidence
- Journal: The Lancet Oncology
- Year: 2018
- DOI: 10.1016/s1470-2045(17)30906-3
- Authors: Teply BA, Wang H, Luber B, et al.
- Findings: A 50 percent decline in prostate-specific antigen on bipolar androgen therapy in 9 of 30 patients (30 percent; 95 percent confidence interval 15 to 49; p less than 0.0001).; Of 21 men who proceeded to enzalutamide rechallenge after bipolar androgen therapy, 15 (52 percent; 33 to 71; p less than 0.0001) had a 50 percent decline in prostate-specific antigen.; The only grade 3 to 4 adverse event occurring in more than one patient during bipolar androgen therapy was hypertension, in three (10 percent).; Single grade 3 or worse events during bipolar androgen therapy included pulmonary embolism, myocardial infarction, urinary obstruction, gallstone and sepsis, one each.; No treatment-related deaths were reported during either bipolar androgen therapy or enzalutamide retreatment.
- What it means: A demonstration that a drug that has stopped working can be made to work again by changing the environment the tumour has adapted to, rather than by changing the drug. It is the strongest clinical evidence in prostate cancer for treating resistance as something reversible.
- Caveats: 30 patients at one centre, single-arm and open-label, with prostate-specific antigen response as the endpoint rather than survival.; Men with more than five sites of visceral disease or bone lesions at risk of fracture were excluded because of the risk of tumour flare; the approach is not safe in symptomatic or high-burden disease.; Cardiovascular and thromboembolic events occurred; supraphysiological testosterone is not a low-risk intervention and needs monitoring.

## Sources

- Lancet Oncol 2018: https://doi.org/10.1016/s1470-2045(17)30906-3
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29248236/
- ClinicalTrials.gov NCT02090114: https://clinicaltrials.gov/study/NCT02090114

## 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/), [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: [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/)
- roadmaps: [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](https://onco.cc/roadmaps/prostate-roadmap/)
- 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: [Enzalutamide](https://onco.cc/drugs/enzalutamide/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- terms: [Bipolar androgen therapy (BAT)](https://onco.cc/terms/bipolar-androgen-therapy/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [PSA (prostate-specific antigen)](https://onco.cc/terms/psa/)
- 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/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- journals: [The Lancet Oncology](https://onco.cc/journals/lancet-oncology/)

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