Differences Between AR-Targeted Therapy in Prostate Cancer

Daniel J. George, MD: I want to get your opinions on the differences between these drugs because we now have 3 drugs in the same class. Obviously, you’re going to pick only 1, and we don’t have head-to-head data comparing these drugs and may not for a while. How do you decide which agent to use? Are there real differences between these drugs, in terms of their pharmacology or biology, that would influence who you might prescribe 1 to versus another? Eleni, do you have any thoughts on that?

Eleni Efstathiou, MD, PhD: This is a great point. I think we would all agree, for the purpose of not going into a lot of detail, that we’re looking at a class of agents that have a very similar efficacy across the board. You can have your personal preference, and then it boils down to how you are going to adapt in your clinic. You would like to be equal in giving all 3 a chance to see how they work, and this is an important thing to take into consideration.

I’m in an everyday practice, not in an academic practice, and I’m going to reach for what I know how to use. We know that 1 of the 3 drugs has been around forever. Ben will speak more to it, but we’ve got a newcomer in here that actually has, in my mind, clearly proven from the preclinical and ongoing data that it does not pass the blood-brain barrier. That may give it an advantage because we all have to admit that the other 2 agents, enzalutamide and apalutamide, do pass the blood-brain barrier. Maybe apalutamide does not as much. That is debatable.

Maybe the ensuing fatigue is less, but then you get a bit more of the rash coming in that has been a nuisance for some of the practitioners. It all essentially boils down to safety. Now you have 1 agent that’s been around for almost 8 years and 2 that are newcomers: apalutamide and darolutamide. I can tell you, I have not used darolutamide a lot. I just started the moment it got approved. I haven’t done any research on it; I’ll be honest. Other colleagues have. I have limited experience to date, and it has been positive. It lives up to the claim of not having as much fatigue.

If you look at the 3 trials and don’t focus on the little details—how much fatigue here or there—but look at the differences in discontinuation due to adverse events versus placebo, that’s your comparator in each of these trials. You’ll see that you do get that difference in percentage in the SPARTAN trial, which is the apalutamide 1. You get the same difference in the PROSPER trial, which is enzalutamide, but there is no difference between the darolutamide arm and the placebo arm when you look within ARAMIS.

It’s about 8.5% discontinuation due to adverse events, which in this case are obviously more associated potentially with disease progression and maybe a bit of darolutamide there. As an overview, until we all get more hands using it, I would say that these data would actually persuade me to reach out and try the darolutamide agent more, especially my older patients. As you said, you want to make sure they’re not going to have more falls or instability in their gait, especially if they also have some backbone of neurological deficit there. I’d like to hear everyone’s thoughts on that.

Daniel J. George, MD: Tanya, I see you nodding your head. Is this your way of thinking, as well?

Tanya Dorff, MD: Yes, I will say that the treatment discontinuation rate is a good tool to judge how much your patient is going to struggle with adverse effects and how often they will get bad enough that they’re going to stop the treatment. There is a difference, I would say. My own experience is that darolutamide is very well tolerated. I don’t see some of those CNS–type effects that I see with the other agents. This is not to say that apalutamide and enzalutamide are not well tolerated. They are, and the quality-of-life data speak to that.

I agree that darolutamide not crossing the blood-brain barrier is significant. In my own practice, it’s not just cognitive, but it’s also sometimes anxiety or depression or just this ill feeling that can lead to discontinuation. I take that to be a CNS effect. Importantly, there are ongoing prospective formal studies to look at cognitive changes, so eventually we will have level 1 evidence that can guide us when we’re concerned about that particular aspect of toxicity.

Daniel J. George, MD: Are there other ways to quantify this kind of stuff. Are there things we can do in our practice to recognize potential risks in our patient population?

Charles Ryan, MD: Absolutely. This is where we need to learn from work that’s being done in the field of geriatrics and neuroscience. There are a lot of tools available to look at cognitive function. Whether we can integrate those into daily practice in an oncology or urology practice is another question. Fall risk is something that has been associated with a couple of these drugs. Assessing the risk for falls is actually quite easy to do.

The timed up-and-go test is very easy. Anyone can do it in any clinic if they know what they’re doing. It’s just having a person walk about 10 feet and back and timing that. We need to get the word out about these tests, provided that we think there is a significant difference among the drugs.

Building on Tanya’s point, we have to do those studies and prospectively look at whether there are differences. If there are, and all the therapies are still available, we have to make those tests available and teach our field how to do those tests so that they can use them in their decision-making. It’s really no different from using a genomics test to make an action.

Daniel J. George, MD: Even if there is not a huge difference between these drugs and it’s a class effect, it’s important for us to recognize because it would factor into our management decisions in these patients. If there are differences by drug, that’s even more important to know going forward.

Charles Ryan, MD: As our patients are living longer, as we just got done saying, and maybe their risk of dying of prostate cancer is slowly decreasing as we give better therapies, attention to these types of factors is more important.

Tanya Dorff, MD: Right. I was just going to say that because it is a class effect and because they’re still on hormone therapy or castration therapy, paying attention to what we can do to mitigate any potential fall risk, for instance, is important. Talking to patients about the importance of exercise and making referrals to physical therapy when appropriate are part of our job as we’re using these agents earlier and longer.

Charles Ryan, MD: And prove to the payer world that these things are worthwhile and should be covered.

Benjamin H. Lowentritt, MD, FACS: Yes. I think from not having the internal medicine background, encouraging our teams to be looking into cardiovascular risk and risk of metabolic disease and other things that we know these agents can contribute to is all part of the same thing. Falls and fractures are the dramatic events that we know we need to avoid, but just because more patients are dying of cardiovascular disease doesn’t necessarily mean that it’s not related to their prostate cancer, since we’re using these agents. Understanding that we have to incorporate all these risk assessments into our practice is definitely a focus.

Eleni Efstathiou, MD, PhD: I want to make that comment, mainly for you, Ben. It’s a matter of streamlining it and building an algorithm. You guys are urologists. You don’t have the time to mess with that. You want to have an algorithm where you send the patient to the cardiologist for a checkup and do the bone density. Breast cancer has done it. Do that bone density every couple of years. Assess the risk of fracture. You don’t even have to do it, but if it’s building the algorithm checklist, you do it.

Benjamin H. Lowentritt, MD, FACS: That’s exactly what we’re trying to do.

Daniel J. George, MD: It’s survivorship, and it’s building in that survivorship model in these patients. No, they’re not cured. But they may not die from prostate cancer, so these are the competing survivorship issues that we have to balance. Thank you, Ben, for bringing that up. It’s a great perspective for urologists, and I like that analogy, Eleni. We can do this in our field as well.

Transcript Edited for Clarity