Selecting an AR Inhibitor for M0 CRPC Treatment

Jorge Garcia, MD:Darolutamide is an androgen receptor [AR] inhibitor. Basically, what it does is inhibits the ability of any ligand to bind to the AR. It is really, to some extent, no different than any of the novel AR inhibitors, such as enzalutamide and apalutamide. But it is a unique agent in the sense that, chemically, the structure is different compared to enzalutamide and apalutamide. And that has, perhaps, an advantage when you look at potential adverse effects.

Efficacy: I think it would be very hard for any of us in the field to say that one agent may be more efficacious than the other agent, in the context of M0 [nonmetastatic] disease, at least with the data that we have from ARAMIS, SPARTAN and PROSPER. Having said that, there are unique features of darolutamide that make this agent distinct from the other 2 AR inhibitors.

When you look mechanistically and chemically at how this agent actually works, one of the unique properties of this agent is that it doesn’t appear to cross the blood-brain barrier. So by default, you may not have some of the adverse effects that are commonly seen in patients who are getting the other AR inhibitors, such as apalutamide and enzalutamide.

There are very similar adverse effects when you look at these 3 oral agents. It’s a class/family effect, if you will, just by virtue of how, mechanistically, these oral agents work by inhibiting AR signaling. There are perhaps 3 unique differences, in my mind, clinically—neurocognitive dysfunction, skin rash, and hypothyroidism. Neurocognitive dysfunction is underappreciated in patients getting enzalutamide. Although the risk of seizure appears to be real for those patients, clinically, I don’t think that’s the No. 1 priority when I think of picking an agent like that. Mechanistically, the difference is that enzalutamide crosses the blood-brain barrier, and therefore can actually compete with neurotransmitters and make people foggy, to some extent, clinically. Clinically, all of us call it something different. Some people call it fogginess, but it’s a slow reaction time, and there is an increased risk for falling, for that matter.

Apalutamide has a bit less, in my clinical practice, at least in my experience, but has a unique adverse effect—skin rash. It’s a nuisance for most patients. It’s not a significant issue, but it is something that actually can impact quality of life for patients in the M0 space, who are healthy people.

Hypothyroidism is also something that has been linked to apalutamide, to some extent. It is something that one needs to know about, but it is easy to manage once you identify that issue. When you look at darolutamide’s adverse effects, you really don’t see the degree of neurocognitive dysfunction that you see with the other 2 oral agents. Perhaps this is a reflection of how, mechanistically, and perhaps, chemically, the structure is so different. You see a small percentage of patients getting hypothyroidism, and the presence of a skin rash is probably in the single digits, probably 2% to 3%. I think those are the 3 unique differences, when you look at the adverse effect profile of this class of agents.

Transcript edited for clarity.