Adverse Events with Next-Generation Androgen Receptor Inhibitors in nmCRPC


Aaron Berger, MD, discusses adverse events with enzalutamide, apalutamide and darolutamide and their management.

Audrey Sternberg: Which adverse events do you typically see with the 3 agents, darolutamide, enzalutamide, and apalutamide? Which are most challenging to manage?

Aaron Berger, MD: The one we typically see most often with enzalutamide is fatigue, or the fancy name would be asthenia. These patients are all on androgen deprivation therapy at baseline. With all the studies, everyone’s on antigen deprivation therapy with either a GnRH [gonadotropin-releasing hormone] agonist or antagonist or had a bilateral orchiectomy. They have very low testosterone at baseline, which can decrease their overall energy level to start with.

Enzalutamide in some patients really zaps their energy substantially, to the point where some people don’t feel like they have any motivation and don’t want to get out of bed. It’s not common that it’s that significant, but I’ve found that sometimes doing a slight dose reduction for patients on enzalutamide will often help with their fatigue significantly. Dropping the dose by 25%, or 1 pill if they’re taking the 4-tablet or 4-capsule regimen, can have a profound effect on their energy levels. In my experience, it hasn’t made a huge difference in their overall outcome as far as the duration of PSA [prostate-specific antigen] suppression. With enzalutamide, or Xtandi, that’s the most common one I see.

With apalutamide, or Erleada, the main one to keep an eye out for is a rash. Those patients can get a rash that can sometimes even be a full body rash. It’s different from a typical drug allergic reaction, where they might get a rash if someone has a penicillin or codeine allergy, they may get hives or a rash within a day or two of taking it, or even after the first dose. This happens on average 2 to 3 months after starting medication. It’s a little different, but something to be aware of. A lot of times, you can treat through it and just give patients antihistamines by mouth or some topical corticosteroids, like Cortaid.

Some patients get a more severe rash. I had a couple of patients with more of a high-grade rash, like a full body rash that required oral corticosteroids and discontinuation of therapy. It’s pretty rare in my experience, but it’s something to be aware of. If patients get a significant rash that you can’t treat through, then you can stop the medication for a couple of weeks. And even if you reintroduce it at the same dose, about 40% of patients won’t get the rash again. That’s something to keep an eye on with apalutamide.

There’s also a slightly higher risk of hypothyroidism with apalutamide. But this typically isn’t something we routinely screen for. It’s mainly patients who have a history of hypothyroidism and are already on medications for thyroid replacement for whom we’ll check TSH [thyrotropin] or a thyroid panel along with their PSA and testosterone, but it typically isn’t something we would check for patients who have no history of hypothyroidism.

Darolutamide, or Nubeqa, which is the newest to market, probably has a very favorable adverse effect profile. It certainly has the risk of some fatigue, although it’s typically less. In the ARAMIS trial, the difference between the placebo and treatment arm didn’t have any major significant differences in any of the adverse events. From a pure adverse event standpoint, the darolutamide—at least per the trials—probably has the least chance of any significant adverse events.

But the bottom line with all of these is that as long as you know what to potentially expect and let the patients know to be on the lookout for, I’ve had great success with all 3 of these medications. They’re all very helpful medications for our patients. And sometimes, like anything else, some people tolerate one better than the other. Like with any medication, sometimes patients will have things like GI [gastrointestinal] upset or muscle aches or joint aches. Sometimes we’ll switch from one to the other to see if we can find an option that gets rid of those adverse effects. But in general, they’re all pretty well tolerated and are very effective.

This transcript has been edited for clarity.

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