Ep. 8: Selecting Optimal AR-Targeted Therapy for nmCRPC

Transcript:

Neal Shore, MD, FACS: We have these 3 drugs now. Enzalutamide is approved in nmCRPC [nonmetastatic castration-resistant prostate cancer] and mCRPC [metastatic castration-resistant prostate cancer]; apalutamide is approved in nmCRPC and mCSPC [metastatic castration-sensitive prostate cancer]; and darolutamide is approved in nmCRPC. For the nmCRPC population, what are your thoughts on scanning and the different AE [adverse event] profiles or comorbidities, drug interactions, and molecular structure? How do you come to talk to patients? They’re not going to really know. They won’t understand. “Well, I’ve got 3 options.” How do you choose?

Alicia K. Morgans, MD, MPH: To address your question on scanning, if it’s regarding the newer molecular imaging techniques, I use them traditionally in the biochemically recurrent hormone-sensitive state. They help me understand if there’s something metastatic that I couldn’t see on conventional imaging that may make pelvic irradiation as a salvage therapy less beneficial to patients if they’ve experienced recurrence after prostatectomy. Otherwise, I would say, I use those minimally because I don’t necessarily have a way to act on them, except in the situation Nancy Ann Dawson mentioned.

I actually make my treatment decisions regarding nonmetastatic CRPC [castration-resistant prostate cancer] based on conventional imaging. That’s how the studies were designed. Even if a patient has M1 disease by molecular imaging, as you mentioned, I still feel that patient can benefit from the drugs that are actually approved in the nonmetastatic CRPC setting. Given the way we see these drugs crossing and spanning the metastatic CSPC [castration-sensitive prostate cancer], nonmetastatic CRPC, and metastatic CRPC settings, there’s benefit across the spectrum. I feel pretty comfortable with that decision.

When I’m trying to choose among those drugs that are available in the nonmetastatic CRPC setting, I think about multiple things. Honestly, I first think about adverse-effect profile. They can be a little different, and they all have their distinct adverse effects. Things like fatigue and hypertension might be more common in enzalutamide; a rash and thyroid problems, as well as some fatigue, may be more common with apalutamide; and darolutamide may still cause a little fatigue. There may actually be falls across the board, but less so with darolutamide. These are all distinct.

When I think about drug-drug interactions, which are another thing Nancy mentioned, there may be fewer with darolutamide. Comorbid disease, adverse-effect profiles, and drug-drug interactions are all things I think about. At the end of the day, I think we have sufficient data showing that it’s worth treating these patients, and that just gets back to the benefit we see across multiple parts of the disease spectrum.

We have new data that we’ll talk about, where we now see, at least for darolutamide and for enzalutamide, that there’s a survival advantage for earlier treatment in the nonmetastatic CRPC setting. There’s benefit. Although the disease space is affected by medical care and may disappear at some point, there does seem to still be benefit in making a choice and using 1 of them—whatever works best for the patient based on comorbidities, adverse effects, and drug-drug interactions.

Neal Shore, MD, FACS: You mentioned there may be some differences with these drugs. All 3 are clearly beneficial in terms of meeting their efficacy end points. All have published good patient-reported outcomes data showing very positive tolerability overall. Yet there are some nuanced differences. You mentioned falls and fractures. William, what are your thoughts? We talked about cardio-oncology. What do you think about neuro-oncology?

William Oh, MD: It’s a very interesting topic, and Alicia has a prospective study that is moving forward in this area. We underappreciate how much damage we’re doing to our patients, partly because it’s hard to measure these effects. We know that when we put patients on ADT [androgen deprivation therapy], they do complain about tiredness, how they can’t remember where they put their keys, and things that we may not appreciate might be interfering with their lives. The vast majority of patients go on with their lives, but there’s a small subset that we’ve seen—even with primary ADT—who are really affected cognitively and from a neurological perspective: their brain, but also their muscles and their overall body functioning in terms of strength. I don’t think we really have fully understood why some patients, whether it’s 5% or 10%, have more adverse effects than expected in that way.

You’re now adding on top of ADT drugs like enzalutamide, apalutamide, or darolutamide in asymptomatic patients, and you’re committing them, by the way, to years of therapy. We can’t forget that they’re exposed to years of additional therapy and that it’s going to affect some of them in a more outsized way. That’s why even though the quality-of-life data with these drugs have looked pretty good, we have to remember that there are going to be some subsets of patients who are going to suffer more. It’s incumbent on the clinicians to really pay attention to this because now that we have 3 options, we could consider switching from 1 to another. I do this all the time in my practice because some patients, for example, may be falling on a drug like enzalutamide.

I’m in New York City, and I had a patient come in once who had been on enzalutamide for a few months, and he said he tripped 3 times. He had a big bruise on his face. He didn’t attribute it at all to the ADT or to enzalutamide. I had to really pull it out of him because he happened to have a bruise that day. Even though the rate of that adverse effect is probably not more than a low percentage, when it happens, we know it can be very profound. It’s just very important to try to balance these, and maybe the adverse-effect profile—as was outlined by Alicia a minute ago—is something we should be paying more attention to for our patients.

Neal Shore, MD, FACS: Just to follow up on that, you’re switching agents while patents have nmCRPC. Will you ever dose reduce or dose interrupt? How do you work that from a practical standpoint?

William Oh, MD: I’ve done both. Certainly, when I had fewer choices, the first thing I would do is stop the therapy and then rechallenge at a lower dose. Now, I have switched some patients from 1 agent to another, because sometimes with dose reductions, they may still have some of those same adverse effects. I think that darolutamide has been an interesting drug. As we all know, there are no cross-study comparisons. All we have is a placebo in each of the studies, and the 1 study that seemed to have a very favorable comparator to placebo in terms of adverse effects seems to be darolutamide. If it is because it doesn’t cross the blood-brain barrier, then that would be very interesting and intriguing for me as a clinician and for my patients.

Transcript Edited for Clarity