Prostate Cancer: Evolving Treatment Approaches - Episode 9

Ep. 9: Neurological AEs and Quality of Life in Treating nmCRPC


Neal Shore, MD, FACS: Alicia, I’ve got to turn back to you because you’re doing so much great work in this area. Talk to us a little about some of the tools, questionnaires, and work that is ongoing in this field of having us better assess neuro-oncological impact.

Alicia K. Morgans, MD, MPH: I think the International Society of Geriatric Oncology really set us up well for these assessments a few years ago, and their recommendations are published in European Urology. This is an international group of experts—some are prostate cancer oncologists, some are neurologists, some are geriatricians—who got together and said, “You are putting patients on these therapies for years. These are elderly patients who have comorbid disease and who are at risk, because they age every day, of having these complications that are associated with aging.”

There’s a very brief assessment, called the G8, that they’ve recommended and we think about. It assesses nutrition, functional status, polypharmacy, and very briefly, cognition as well. We could think about putting that into our practices, as well as something called the Mini-Cog, which includes 3 questions. It takes less than 5 minutes to administer and can be done by an MA [medical assistant]. It is a way to briefly assess cognitive function. But in reality, it’s really hard in clinical practice to get all these assessments done. Although these have been outlined and seem reasonable, they are very basic screening tests where if you uncover something, you actually have to send patients to a specialist to perform an in-depth neurological evaluation and an evaluation of potential social services that may be helpful—physical therapy, aid for whatever the deficit is.

We are at the beginning stages of trying to understand this. Ask a patient about his fall or his bruise, or ask a patient—or a caregiver, who will sometimes give more information—how are you feeling? How is your mood? How are you getting around? What does your day look like? These simple questions can help us identify cracks in their facade because patients usually come in and tell me, “I feel great. I feel fine.” But if you start picking at certain things—even by asking how their thinking and memory are—patients will answer these little questions in a way where even if they say, “I’m fine,” you can identify ambiguity that you can dig into and find that there are problems.

It does start with us, whether it’s a standardized assessment—which is ideal because if you ask everyone in a standardized way, you’ll probably uncover the most problems—or just following our intuitions and hunches and asking these basic questions. How are you thinking? How are you feeling? What does your day look like? We can start to uncover some of these issues.

Neal Shore, MD, FACS: Pedro, what about yourself? You have these patients who come in to your busy clinic. They could be in the VA [Veterans Affairs] hospital. They could be in outlier clinics as well as in a metropolitan health center. How are you thinking about not only the tolerability of these drugs but also proactive ways of working through their ADT [androgen deprivation therapy], their AR [androgen receptor] inhibitor, or their neurocognitive impacts? Any strategies?

Pedro C. Barata, MD, MSc: I usually go back to Alicia and others’ work on that to help me in terms of safety signals and red flags that I’ll identify. The reality is that if you don’t ask, you won’t find out. Even when we conduct these really nice studies, the discontinuation rate was close to 10%, which tells us that most patients on these medications will do fine, but there’s a subset of patients who won’t, unfortunately. The question is, can we really identify who those patients are? Are we paying enough attention to them? I think that’s critical. Perhaps when that happens—rarely, but nonetheless, those are real patients—we have to sometimes consider discontinuation of medication and think about ways to improve impact on the neurocognitive system. We talked a little about cardiovascular impact, and now we’re talking about the neurocognitive impact. Those are real cases. I would argue that they are infrequent but real nonetheless.

I would just like to make a point in terms of efficacy. I think we all stress the point of—and really, we’re talking a lot about—treatment intensification, or using these agents early on. Whether we use a more complex scan and diagnose metastatic disease sooner rather than later, the reality of it is what’s going to change. Are you going to start to use the antiandrogen on top of ADT, or are you going to debate use of the CYP17 inhibitor instead?

Alicia just mentioned the press release that came for darolutamide and enzalutamide in terms of survival benefit, and we all predict that we are about to see the same with apalutamide. I think it’s the same across the board that when we take a step back and look at this as an overall picture, we are thinking that unfortunately, a lot of these patients will progress. We are not aiming for cure, but we’re aiming to control the disease and make prostate cancer as much a chronic disease as we can. Unfortunately, most of these patients will face mortality. It’s always a difficult balance between what I can do to help them live longer and, at the same time, preserve quality of life as much as I can.

Nancy Ann Dawson, MD: I think that’s a really important point because as William mentioned, his patient didn’t even want to mention that tripping might have anything to do with the medication. I find that my patients don’t want to tell me that there is an adverse effect. Many of them—not all of them—don’t want to tell me about adverse effects because they don’t think they have any other option. They say, “You put me on this to make me live longer, and I want to live longer. I guess I’ll just have to put up with this.” One of the good things about having multiple drugs is that you can actually switch between them. Let’s say someone did fall or is a little sleepier or more confused on 1 drug. If you switch to darolutamide, which doesn’t cross the blood-brain barrier, maybe they won’t have as much of a problem.

I’ve seen that that’s true. The patients are really happy to know that they might have another option so that they can tell you something’s wrong. You don’t have to tease it out. We can, as you said, try a lower dose or try a different drug. Once they realize they might have another option, that’s also very important and allows them to feel more comfortable telling you that instead of this drug you’ve given them to save their life, there might be another 1 you can try instead.

Neal Shore, MD, FACS: I think that’s a great point.

William Oh, MD: I do want to emphasize the importance of the overall survival [OS] benefit. We haven’t seen the data yet, but it wasn’t always intuitive that if you use a drug earlier, the patient is going to live longer. To me it’s extremely powerful. MFS [metastasis-free survival] is a clinically meaningful end point. As I mentioned earlier, you’re giving patients 2 years or more of additional therapy, and you’re preventing a metastasis. But if in the end they all die at the same rate, then have you really used these drugs for the purpose of allowing them to live longer? I agree with Nancy that patients want to live longer. Of course, they don’t want to live badly. But in the end, they want to live longer, and we want our patients to live longer.

It’s quite powerful because these drugs have been around. Drugs like enzalutamide and abiraterone have been around for many years now in the metastatic CRPC [castration-resistant prostate cancer] setting. Shifting them to earlier use and still having them associated with an overall survival benefit is a very powerful statement that earlier use of these drugs is really meaningful in terms of OS.

Neal Shore, MD, FACS: I think this was a big deal. There were press releases. We haven’t seen the data, but they’re going to be presented. PROSPER and ARAMIS—darolutamide and enzalutamide, respectively—have reported as achieving not only MFS but also the secondary OS end point. I think it’s really a big advance. As you said, I suspect apalutamide will report this as well by the end of the year.

Transcript Edited for Clarity