How abiraterone acetate actually works in advanced prostate cancer


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.

The structure of ketoconazole

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.

The structure of abiraterone

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.

It may be entirely inappropriate to give abiraterone to a man with prostate cancer who is not medically or surgically castrate. But even if that is the case, one still has to ask whether combining standard hormone therapy with abiraterone + prednisone might be more effective in combination with radiation therapy than standard hormone therapy alone for patients with high-risk, locally advanced prostate cancer. A small, pilot Phase II trial to investigate this question is already recruiting patients in Seattle. Another question that may need to be asked is whether early use of short-term medical castration in combination with abiraterone + prednisone may be able to completely shut down prostate cancer growth for long enough to put some patients with progressive disease into truly long-term remission. These questions will need to be investigated with great caution. It would be very unwise of us to over-use a drug like abiraterone too early in the disease state and lose its potential benefits for men with late stage disease. There are plenty of clinicians who already think we over-use standard hormone therapy in such a manner (as discussed on this web site just a few days ago).

18 Responses

  1. Mike

    Thanks. Very helpful information.

    Bill

  2. Many thanks.

    rd

  3. I’ll add my thanks.

    Is the abiraterone with low-dose prednisone given for just a short time, or intermittently? If not, would there not be substantial side effects from the low-dose prednisone?

    Even though I have some concerns about the drug, which hopefully will be relieved as knowledge replaces ignorance, I can’t help feeling about the mechanism: this is really cool!

  4. Jim:

    To date the only information I am aware of is in the use of abiraterone continuously with low-dose prednisone, but we are still very early in the understanding of the potential uses of this drug in day to day practice. And yes, there are certainly side effects associated with the long-tern use of low-dose prednisone.

  5. Very interesting stuff.

    This begs the question of diet as a mechanism to manage the creation of the secondary androgens which convert into testosterone and dihydrotestosterone.

    Any dabbling in this area or other web sites which might provide information?

  6. We really have no well-established understanding of the impact of diet on levels of secondary androgens. The studies that have been carried out are largely based on selectively bred laboratory animals, and have limited applicability to human beings. The variations in the way that humans process food are enormous, so what may apply to some men may have no application to others, etc. There is no specific evidence that I am aware of that a vegetarian or even a low-fat diet has replicable impact on the circulating levels of secondary androgens in men who are already being treated with standard forms of hormone therapy, etc.

    A lot of people believe — very strongly — that certain types of diet can impact their prostate cancer progression (or at least their PSA levels) over time, but the concrete scientific evidence in support of these beliefs is sparse at best. You can probably find all sorts of information on the web with opinion on this matter. But that it largely what it is — opinion, and not evidence-based science.

  7. DIET FOR COUNTERING ANDROGENS

    I’m replying to Pat 2/20/2011 at 10:17 am with the context of Sitemaster’s reply of 2/20/2011 at 11:09 am. I’ve been dealing with a challenging case of prostate cancer for over 11 years, relying on intermittent, maintained triple androgen deprivation therapy, but also bolstered by diligent use of those nutritional tactics for which we still lack thoroughly convincing data. I’m doing very well. I wanted to highlight two tactics in particular, pomegranate (looks effective) and saw palmetto (looks ineffective for cancer).

    We have just had a key second Phase II study reporting success in slowing PSA doubling time with pomegranate, this time the extract instead of the juice. In a recent 2010 cell-line study, researchers at Laval University in Quebec found that punicic acid, a dominant component of pomegranate seeds, inhibited DHT and PSA production. If the work holds up in humans, it probably explains some of the success associated with quality juice and extract from pomegranates.

    Saw palmetto is a different story. First, the quality of saw palmetto extract has been highly variable in previous research surveys, with some supplements containing virtually none of the extract despite being labeled as saw palmetto extract. However, saw palmetto is classed as a 5-alpha reductase inhibitor. The 5-ARI drugs finasteride and Avodart (dutasteride) both sharply curtail conversion of testosterone to DHT, which is generally recognized (Dr. Patrick Walsh excepted, perhaps some others) as being the dominant androgen for prostate cancer. However, some research has suggested that saw palmetto’s 5-ARI function is probably somewhat different and milder. While quality saw palmetto (particularly Permixon) is able to help with urinary function and can shrink the prostate a bit, some research suggests it is not effective against prostate cancer. On the other hand, other research suggests there may be some benefit from saw palmetto against prostate cancer if it can produce a substantial reduction in DHT, but my take is that the evidence is quite preliminary.

    A web site many of us use in looking at the data on such questions is PubMed (Public Medicine), which is part of the National Library of Medicine under the US National Institute of Health. To give my memory much needed refreshment, I searched the site for “saw palmetto AND DHT” (without the quotation marks).

  8. Dear Sitemaster:

    En efecto, mi padre está tratándose con abiraterona, de uso compasivo, es decir, se puede comprar directamente a la empresa comercializadora del fármaco.

    Después de 1,5 meses, el PSA le ha bajado de 1.400 a 732, las dolencias oseas le han disminuido, somos muy optimistas al respecto.

    Cada pote contiene 120 pastillas de ABI, se tiene que tomar 4 al dia junto con 5mg de prednisona.

    Julio

  9. Julio:

    No sé donde vives, y me alegro de saber que abiraterona parece estar trabajando para su padre. Sin embargo, hasta donde yo sé abiraterona no ha sido aprobado para la prescripción en cualquier parte del mundo, excepto como parte de un ensayo clínico, por lo que me pregunto si el abiraterona que se están vendiendo en realidad es legal.

  10. Estimado Sitemaster,

    Me gustaria saber donde se puede comprar abiraterona para uso compasivo como menciono Julio, en su comentario. Es posible que un doctor de Bolivia pueda solicitar o comprar este medicamento? Muchas gracias.

    Esperanza

  11. Querida Esperanza:

    Lo siento, pero no sé si la forma en que es posible obtener acetato de abiraterona en Bolivia. Le sugiero que se comunique con el centro más cercano de cáncer, sino que debe ser capaz de ayudarle.

  12. I have been taking abiraterone for 3 months now and due to the cost factor I am planning on stopping the use of it. What is the impact of me stopping?

  13. Dear Michael:

    I can only assume that, if the abiraterone has been controlling the progression of your cancer, if you stop taking it your cancer will start to progress again.

  14. My Father was advised to start abiraterone + predisone 5 mg from tomorrow (8th March 2013), All the above information helped a lot in understanding these drugs. Thanks a lot

  15. Dónde puedo comprar este medicamento? en mi país Chile, no lo vende el laboratorio sino una entidad farmaceútica y valor US$4,050 dólares americanos los 120 comprimidos, que sólo es para un mes de tratamiento

  16. Lo siento, pero no sé cómo ayudarte. Aquí en Estados Unidos este fármaco cuesta casi US$6,000 dólares por mes.

  17. As someone who had several months on abiraterone + prednisolone, after a few months of docetaxel, I regrettably have to report that my PSA spiralled during this treatment (40 up to over 1000), and scans revealed no improvements.

    I then tried a couple of other so-called magic chemo treatments with no success, until recently doing 5 rounds of cabazitaxel, where the PSA varied from 800 to 1,400, but the most recent scan seems to have revealed a significant reduction of the main tumour (in my liver) and in my bones.

    Neither my consultant nor I understand what is happening, and where I go from here. I don’t feel happy continuing with cabazitaxel, since the side effects were having a dire effect on my QOL. Anyone else had these contradictory signals?

  18. Dear David:

    There are patients who don’t respond to any of the newer drugs very well. One reason for this can be that these patients have undiagnosed neuroendocrine prostate cancer or NEPC, which we now know occurs in up to about 25% of men with mCRPC. Has your consultant even discussed this possibility with you? Have a look at this link.

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