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How abiraterone acetate actually works in advanced prostate cancer

Posted Jan 25 2011 12:00am

A regular reader of this column asked us to provide a “layman’s summary” of how the investigational drug abiraterone acetate actually works to delay the progression of metastatic, castration-resistant prostate cancer (mCRPC). So here you go

The easiest way to think about abiraterone is as a “better” ketoconazole. For many years ketoconazole has been used in the treatment men who had progressive prostate cancer and who seemed to have “stopped responding” to standard forms of hormone therapy like LHRH agonists (e.g., leuprolide acetate/Lupron) and antiandrogens (e.g., bicalutamide/Casodex). Ketoconazole works in such patients because of a reversible effect on an enzyme called CYP17A1 (properly known as 17α-hydroxylase/17,20 lyase) and commonly just known as CYP17.

Originally, it was believed that if patients were dosed with high enough levels of ketoconazole, it could temporarily slow down the normal processes by which CYP17 can convert the “secondary” androgens like androstenedione and dehydroepiandrosterone (DHEA) which are made in the adrenal glands into testosterone and dihydrotestosterone (which are the hormones that stimulate the growth and proliferation of prostate cancer cells). However, …

Back in 2008, Locke et al. were able to show that in an animal model of mCRPC –  CYP17 also facilitated the conversion of cholesterol into a whole range of these secondary androgens and thence to testosterone and dihydrotestosterone. In other words, even when standard hormone therapy had all but stopped the conversion of testosterone to dihydrotestosterone by traditional mechanisms (surgical and medical castration), new testosterone and dihydrotestosterone was potentially being created by other mechanisms.

Now the basic difference between ketoconazole and abiraterone acetate is that abiraterone is a specific (“selective”), potent, and irreversible inhibitor of CYP17. When ketoconazole binds to CYP17 it can come unbound again, and the amount of ketoconazole bound to CYP17 molecules depends on the concentration of ketoconazole in the cell with the CYP17 at any point in time. By contrast, once abiraterone acetate binds to a molecule of CYP17, that particular molecule of CYP17 is permanently disabled.

Because abiraterone effectively “shuts down” the effects of CYP17, abiraterone must be given with a low dose of a glucocortiocoid (e.g., prednisone) in order to avoid side effects that would otherwise result from a build up in the concentration of another hormone called adrenocorticotropic hormone.

Now what we don’t really know yet is what happens if you give a man with prostate cancer the combination of abiraterone + prednisone much earlier in the disease state or what happens if you give abiraterone + prednisone to a man who is not medically or surgically castrated. We do know that response to abiraterone therapy in men with mCRPC appears to be better in the men who have high circulating levels of adrenal androgens in their blood.

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