Is combining abiraterone acetate with MDV3100 going to be clinically beneficial in mCRPC?

An article just published in Cancer Research this week suggests that adding the investigational agent enzalutamide (MDV3100) to abiraterone acetate and prednisone in men being treated for metastatic, castration-resistant prostate cancer (mCRPC) may be able to further delay disease progression among men showing signs of progression after initial treatment with abiraterone acetate.

The article by Richards et al., which is also discussed on the web site, goes into detail about why patients start to become refractory to treatment with abiraterone acetate. The authors suggest that this is a consequence of the co-administration of one of the glucocorticoids (prednisone or prenisolone) that are given to help prevent possible side effects of abiraterone acetate.

These are very preliminary laboratory (as opposed to clinical) data, and will require careful study in clinical trials. Indeed, the authors actually discuss three quite different ways in which it may be possible to counter the impact of glucocorticoid stimulation of mutant androgen receptors in men with prostate cancer:

  • By simply increasing the daily dose of abiraterone acetate
  • By addition enzalutamide to the therapeutic regimen
  • By adding an older (generic) antiandrogen, bicalutamide, to the therapeutic regimen

The bottom line is clearly that therapy than inhibits the activity of the CYP17A1 enzyme and similarly inhibits androgen receptor binding may be able to extend the activity of simple treatment with abiraterone acetate. A more fundamental question, however, may be whether treating patients with enzalutamide before initiation of abiraterone acetate therapy may have the same or even better effects. As we have said several times before, we are only at the beginning of starting to understand how best to use and/or sequence these new drugs in the management of castration-resistant prostate cancer. There are few useful data to provide us with good guidance at this time.

2 Responses

  1. Abiraterone is in trials now without prednisone so the thinking presented here must have some validity.

  2. If resistance to Zytiga is mediated by the prednisone then a much simpler solution would be to use Zytiga as a single agent without prednisone. Abiraterone (Zytiga) was tested as a single agent in the Phase 1 clinical trials and found to be safe up to a dose of 5000 mg daily. Single agent Zytiga makes much more sense than combining with additional medications. This could work out very expensive and — presuming enzalutamide (MDV 3100) will cost the same as Zytiga — the proposed Zytiga / enzalutamide combo would cost $10,000 dollars per month.

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