DR BEER: We call these drugs antiandrogens or androgen receptor blockers. And the words make it sound so simple, but that’s not exactly what happens at a biologic level.
Many of these agents, similar to some of the hormonal agents in breast cancer, can have both agonist and antagonist actions. And bicalutamide, which we rely on to be an antagonist, also has some paradoxical agonist activity. So 1 difference between the 2 drugs is that, at least today for enzalutamide, we’ve not seen any evidence of any agonist actions of the androgen receptor.
One possible explanation for that is that unlike bicalutamide, enzalutamide binds to the AR, the androgen receptor, in the cytoplasm and either prevents or substantially reduces its ability to move into the cell nucleus where the DNA resides and where androgen receptor and other nuclear receptors regulate the expression of genes and do what they do. So it blocks it outside of the hot zone, if you will, of the nucleus and doesn’t let it go in there.
DR LOVE: I have a list of questions that we’ve received from medical oncologists, and Matt, if CYP17 is required for androgen biosynthesis, why do we need a GnRH analog with abiraterone?
DR SMITH: That’s a good question. One would wonder if you could use abiraterone acetate monotherapy to achieve perhaps for profound hypogonadism. The problem is that there’s feedback. This is a complex regulatory system and there’s feedback. And so you would require increasing doses of abiraterone to achieve consistent low testosterone levels in an intact man. And that would diminish the therapeutic index of the drug, so that’s not a desirable approach.