DR OH: The androgen biosynthesis inhibitors block 2 lyases in the pathway to develop
the adrenal sex steroids. When you block those 2 enzymes, there’s a feedback mechanism that increases the amount of cortisol made in the alternate pathways. And that, unfortunately, leads to complications like hypertension and abnormalities in potassium metabolism.
So in order to overcome that, actually using supplemental steroids like prednisone seems to abrogate that response.
With orteronel, there’s some evidence that maybe that feedback mechanism is maybe less of an issue, but, in fact, the addition of supplemental steroids does, in fact, reduce the risk of hypertension, for example, and other mineralocorticoid effects.
DR LOVE: Oliver, any other comments in terms of what we know about resistance to androgen deprivation or other forms of endocrine treatment?
DR SARTOR: Great question. There’s a lot that we don’t know here, and it’s an extremely active area for research. Based on the paper from MD Anderson, trying to be able to determine was there androgen present after the “implication” of abiraterone? It turns out that it was almost undetectably low. It was extremely, extremely low, implying that there may be nonandrogen access, ways of activating the tumor cell or, alternatively, that you have a ligand-independent androgen receptor.
There’s been some very interesting work with what’s called the “splice variant,” where you truncate the androgen receptor and lose the ligand-binding domain, yet you still have an active androgen access. So now you have ligand-independent androgen access, and you see these PSAs go up, and the surge implies that the androgen receptor target genes remain upregulated but you don’t have ligand. So there’s a lot more work that we have to do, and it’s a very, very interesting area, lots of research right now. And I think we may end up being able to make progress in the next several years.