DR SMITH: So the drug crosses the blood-brain barrier, and it’s almost certainly a class effect. There’s some binding together, receptors, and so it’s a near target effect. And it’s likely a class effect. It was seen in another drug candidate from another sponsor, that was stopped early due to CNS toxicity. So it’s almost certainly a class effect.
DR LOVE: Was it seen with bicalutamide?
DR SMITH: No, but that’s a weak antiandrogen. It too, though, does cross the blood-brain barrier. But in development of other highly active AR antagonists, this type of adverse effect was seen in an early drug candidate for another company.
DR BEER: So from a mechanism standpoint, there’s a chloride channel that’s being blocked in the brain that’s thought to be related to seizure threshold. And in animal models, seizures have actually been seen with other agents in this class, including nilutamide. I don’t think with bicalutamide. In humans, I’m not aware of nilutamide-induced seizures. So it’s probably a dose-related effect. And enzalutamide is just slightly over the threshold, so we see it in 1 in 100 patients or so, and we don’t see it so much with nilutamide. But there is an explanation. It’s not a random effect.
DR PETRYLAK: I think that those are very valid points, but when you look at the 5 patients, I believe, who had seizures, there were reasons why they could have had a seizure. One was an alcoholic, if I remember correctly. The second had a documented brain metastasis. So there are reasons why this could have occurred apart from the mechanism we’re talking about.
DR SMITH: If I could add that I accept that comment, but there’s a tremendous bias in reporting, right? So they didn’t go back and look at all the patients who didn’t have seizures to find out how many of those patients were alcoholics. They didn’t do MRIs of the brains to find out how many patients had brain metastases who didn’t have seizures.
The study was, in fact, designed to exclude patients who were at risk for seizure. It excluded a variety of other concomitant medications, any patient with known dural or CNS metastases. So I think we do have to be careful about being cavalier about this issue, particularly as the drug is applied to a broader population. I’m very enthusiastic about the drug, but we really need to remind everyone about the potential risk for this issue, particularly when it’s rolled out to a general population, which, guess what, a lot of these men drink. Most of them haven’t had prior CNS imaging. They’re on a variety of other concomitant medications that would have been excluded in this trial. So it’s just worth keeping in mind.
DR LOVE: Just as long as you mentioned imaging, I’m guessing that you wouldn’t necessarily image the brain before you start the drug, or would you?
DR SMITH: We would not routinely do CNS imaging in the typical patient without symptoms. And I don’t intend to begin doing so in all patients who go onto enzalutamide. But this just speaks to the need for some caution about use of any of these agents.