Charles J. Ryan, MD: Darolutamide is an orally available androgen receptor antagonist. It is different from enzalutamide and different from apalutamide. Those 2 drugs were actually developed using a bicalutamide backbone. They’re chemically related to bicalutamide. Darolutamide is not related. It has a different structure. And as such, it may have a different profile. It looks really good in terms of its phase I and II data in terms of disease response. In fact, if we were to take the phase II data in CRPC with darolutamide and put them side-by-side with the phase II data from apalutamide, they look very, very similar.
One area where darolutamide may actually have an advantage, certainly over enzalutamide, would be a reduction in CNS toxicities. Many patients who take enzalutamide experience a significant amount of fatigue. There’s also some concern about cognitive function and even falls that occur with enzalutamide. Now interestingly, many patients who take enzalutamide have none of those problems. There’s probably a group of patients who are at risk for these problems, which is something that we’ll be exploring. However, with darolutamide, with the lower degree of CNS-CSF penetration, we might see patients who, even if they are at risk for some of those cognitive problems, don’t experience the problem.
Judd W. Moul, MD: Darolutamide is another novel oral antiandrogen that’s currently in phase III trials to determine its effectiveness for M0 CRPC. So theoretically, we’ll talk about enzalutamide and the trials that are ongoing for that approval in M0 CRPC. We’ll talk about apalutamide and its trials. And now, this third key drug is darolutamide, or ODM-201. This is a drug that is being developed by Bayer Pharmaceuticals, and it’s being developed in the exact same way, essentially, that apalutamide is being developed, some very similar phase III trials, other than the fact that darolutamide has come along a little bit later, will likely not complete the trials for a couple more years, and likely will not get to market as soon as enzalutamide or apalutamide.
Darolutamide is also a novel oral antiandrogen. The slight difference is that it seems to be effective not only against the wild-type androgen receptor but also mutated versions of the androgen receptor. And what that means clinically, at least what people believe, is that since it works against these mutated androgen receptors, the theory is that it may be slightly more effective in the long run than either apalutamide or enzalutamide. However, that remains to be proven.
The other interesting thing is that it has a novel chemical structure, novel configuration, such that the drug does not cross the blood-brain barrier to any significant degree. So, people in the field feel that because it doesn’t cross the blood-brain barrier, it might have less toxicity than apalutamide or enzalutamide. Specifically, less fatigue and less falls, and certainly less risk of a seizure. Now, that is theoretical and needs to be borne out in the phase III trials. The drug was developed a little bit later. It’s a newer drug, so we don’t have the robust phase III data yet that we do for apalutamide or enzalutamide.
Charles J. Ryan, MD: Darolutamide, like apalutamide, would represent a further incremental improvement in androgen-receptor targeting, perhaps with a better profile. Perhaps, because of its different structure—and we don’t know the answer to this—it’s going to have clinical efficacy in some patients who have experienced progression on enzalutamide or apalutamide. It’s too early for us to know that yet, but that’s something that would need to be explored.
Transcript Edited for Clarity