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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.
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.
In plain words · The hormone switch that drives prostate cancer, attacked by castration and by pills that block the receptor.
Showing the target this term concerns: Androgen receptor.
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 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.
Shares PSA50 / PSA90 response, TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer, Castration-resistant prostate cancer (CRPC) and the tags gu, prostate-glossary.
Shares AR-V7 splice variant, Castration-resistant prostate cancer (CRPC), Androgen receptor, Acquired resistance to every therapy and the tags gu, prostate-glossary.
Shares Androgen deprivation therapy (ADT), Quality of life, Androgen deprivation therapy (ADT), Prostate cancer and the tags gu, prostate-glossary.
Shares Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer, Castration-resistant prostate cancer (CRPC), Trial design, endpoints and cost, Prostate cancer and the tags gu, prostate-glossary.
Shares AR-V7 splice variant, Acquired resistance to every therapy, Metastatic castration-resistant prostate cancer, Prostate cancer and the tags gu, prostate-glossary.
Shares Quality of life, Toxicity and quality of life are undervalued, Prostate cancer and the tags gu, prostate-glossary.
Shares Metastatic castration-resistant prostate cancer, Prostate cancer and the tags gu, prostate-glossary.
Shares Trial design, endpoints and cost, Prostate cancer and the tags gu, prostate-glossary.