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Giving men with castration-resistant prostate cancer large doses of the hormone the treatment has spent years removing makes a third of them respond, and makes half of them respond again to the drug that had stopped working. It has never been taken to a definitive trial, partly because the endpoint that shows the benefit is not the one trials usually use.
RESTORE gave monthly testosterone cipionate 400 mg to 30 men who had progressed on enzalutamide: 9 of 30 (30 percent) had a 50 percent prostate-specific antigen fall, and 15 of 21 (52 percent) responded when re-challenged with enzalutamide afterwards. TRANSFORMER randomised the approach against enzalutamide in 195 men and found progression-free survival of 5.7 months in both arms, but progression-free survival through crossover of 28.2 against 19.6 months in favour of testosterone first (hazard ratio 0.44, P equals 0.02), prostate-specific antigen progression-free survival on enzalutamide of 10.9 months after testosterone against 3.8 months after abiraterone, and quality of life consistently favouring testosterone.
The drug is an old generic. There is no commercial sponsor with a reason to run the trial, and the primary endpoint that regulators are used to, progression-free survival on the assigned treatment, is precisely the one on which the approach is flat, because the benefit is resensitisation rather than direct cytotoxicity. That combination is why a treatment with a randomised signal and a quality-of-life advantage has sat at phase 2 since 2021. The proposal is a publicly funded phase 3 in asymptomatic men with low-volume castration-resistant disease, powered on progression-free survival through the second line, with overall survival and patient-reported outcomes as key secondaries.
UK and NHS specifics (the National Screening Committee position, NICE technology appraisals and their recommendation numbers, Cancer Drugs Fund status, magnetic resonance imaging and radiotherapy capacity, National Prostate Cancer Audit indicators and trial access) belong on the UK and NHS page for prostate cancer and are not restated here.
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.
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.
The first predictive resistance biomarker in prostate cancer, and a mechanism rather than a correlation: a receptor with no ligand-binding domain cannot be blocked by a drug that binds the ligand-binding domain. It is also the origin of the case for androgen receptor degraders, which destroy the protein rather than blocking a site the protein no longer has.
The design specification for the second-generation antiandrogens. A drug for castration-resistant prostate cancer has to stay an antagonist when the receptor is abundant, which is what enzalutamide, apalutamide and darolutamide were engineered to do and what bicalutamide fails to do.
The first evidence that resistance to hormone therapy in prostate cancer is an adaptation of the target rather than an escape from it, which is why the field kept building better androgen receptor drugs instead of abandoning the pathway.
Shares Molecular determinants of resistance to antiandrogen therapy, Quality of life, PSA (prostate-specific antigen), Enzalutamide and the tag prostate-evidence.
Shares Rotate between drugs on a fixed schedule instead of waiting for failure, AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Bipolar androgen therapy (BAT) and the tag prostate-evidence.
Shares Molecular determinants of resistance to antiandrogen therapy, PSA (prostate-specific antigen), Abiraterone acetate, Castration-resistant prostate cancer (CRPC) and the tag prostate-evidence.
Shares TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Intermittent androgen deprivation (IAD), Quality of life, PSA (prostate-specific antigen) and the tag prostate-evidence.
Shares In vivo amplification of the androgen receptor gene and progression of human prostate cancer, Castration-resistant prostate cancer (CRPC), 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, Androgen receptor and the tag prostate-evidence.
Shares PSA (prostate-specific antigen), Enzalutamide, Castration-resistant prostate cancer (CRPC), 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 and the tag prostate-evidence.
Shares Quality of life, PSA (prostate-specific antigen), Castration-resistant prostate cancer (CRPC), 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 and the tag prostate-evidence.
Shares PSA (prostate-specific antigen), Castration-resistant prostate cancer (CRPC), 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, Acquired resistance to every therapy and the tag prostate-evidence.