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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday here at ASCO GU 2025. And an especially well-known guest—I can't even call her a guest—Alicia Morgans, Associate Professor, Harvard Medical School, Dana-Farber, extraordinary researcher and UroToday regular. Welcome, Alicia.

Alicia Morgans: Thank you so much, Oliver. I appreciate it.

Oliver Sartor: So it's interesting, because you're often doing the interview and I might be on the other side, but this time we're switching sides. And you have a really interesting study on cognitive changes in men. And before we get into the exact study, I'd like to give a little bit of background. What you're going to be looking at is abiraterone and enzalutamide and some cognitive effects, which you're going to manage quite well. But why did you start this study? What was the genesis of the study? Where did the support come from, before we get into the results?

Alicia Morgans: Sure. So I think the idea for this study actually started back in 2014, 2015. There were actually multiple publications coming out describing in real world populations, and one prospective study from Moffitt describing in a prostatectomy-treated cohort, some of them treated with ADT, that there may be some cognitive effect, cognitive decline associated with androgen deprivation therapy in patients with prostate cancer.

So certainly, this was something that I was thinking about. I think a lot of people have been thinking about it in their clinics, especially since we use medications that really intensify that low testosterone state, including in places like the central nervous system in the brain. And there was actually a lot of talk at that time, too, because enzalutamide was a relatively newer drug. We knew that it crossed the blood-brain barrier, as evidenced by the low rate of seizure in some of the studies. And we also knew that some patients seemed to have some fatigue or some just slowness about them, at least in my clinical practice.

And so as I was thinking about all of these things, I put together a grant application, and the Prostate Cancer Foundation funded it through the Durden Family Award. It was a creativity award and the first grant I ever got, so very, very exciting, in about 2016. So this study that we're presenting at GU ASCO 2025 has been in process for a long time and has been a labor of love. And really a question, I think, that a lot of us have been wondering about in our practices, including mine, over time.

Oliver Sartor: Very provocative beginning going back a decade. So let's talk about the study. Let's talk about the design, the participants, and the outcomes. So give us a little sort of synopsis for our listeners.

Alicia Morgans: Sure. So the study is really an assessment of patients with metastatic castration-resistant prostate cancer who are receiving abiraterone acetate and prednisone, in addition to their ADT, or enzalutamide, in addition to their ADT. The study was designed initially to be a randomized trial, but because of feedback from folks who were going to be involved in putting patients on study, they really encouraged me to make it a nonrandomized trial because people, even at that time, had strong preferences about which patients they might want to put on abiraterone or enzalutamide.

So it ended up being a nonrandomized trial in mCRPC for these two agents that clinically, we expect to control the disease similarly. But we thought maybe there was a difference in cognitive function, because as I said, enzalutamide is an androgen receptor antagonist, including on androgen receptors in the central nervous system, whereas abiraterone acetate is a steroid synthesis inhibitor that just lowers testosterone production. So there was an expectation that if we were inhibiting testosterone receptors in the CNS, we might see more cognitive effects than if we just lower testosterone more.

In any event, nonrandomized trial. We expected and hoped to get 50 patients per treatment arm, and we were following them over the course of a year using patient‑reported outcome measures for cognition, fatigue, and other activities of daily living, as well as computer‑based cognitive tests where we were studying multiple domains of cognitive function, from executive functioning to working memory and visual‑spatial activity, as well as pen‑and‑paper‑based cognitive tests, because there's still controversy in the cognitive testing world as to whether pen‑and‑paper tests may better capture cognitive function than computer‑based tests.

So we did all of these batteries on these poor men who enrolled. I would say that we were only able to actually get 51 patients on the abiraterone arm and 23 patients on the enzalutamide arm, despite having many years of enrollment. Because of all the testing and the lack of a novel drug, it was an incredibly altruistic act for these patients to participate in this trial. As you know, you had the study open at Tulane and had patients going on this study.

But that's what we ended up getting in terms of numbers. So we did not quite meet accrual goals despite being open actually for a number of years, and all of the intensity of all the investigators at sites who really tried to get people on.

Oliver Sartor: So castration‑sensitive. Everybody gets the ADT and physician choice and probably influenced a little bit by patient choice, because patients, physicians often work together.

Alicia Morgans: Absolutely.

Oliver Sartor: And you were putting patients on, and then let's talk about the assessment timing, just so I can have a little bit of feeling. Did you get a baseline before they started on the ARPI? So you had baseline, and then repetitive testing. And so go through those results a little bit for us.

Alicia Morgans: Sure. So at baseline, we had baseline cognitive testing, as well as patient‑reported outcomes. We also had an assessment of education level and an assessment that really tried to investigate their current function and activities of daily living. And then we followed them with testing every three months. That included all of the batteries that I talked about. So we had baseline, three months, six months, nine months, and 12 months of each of those testing time intervals.

Oliver Sartor: Got it. What did you find?

Alicia Morgans: Sure. So what we found is that patients were relatively similar at baseline and had really quite minimal change in terms of that objective cognitive testing by computer‑based tests over the course of 12 months. We also found that there was really not a substantial difference between the arms, again, talking about the objective cognitive test. And that was the primary endpoint.

So the message there, and the information that we learned, is that there's minimal measurable change on objective cognitive testing in that short term, at least one‑year period of follow‑up, and not a significant difference between the treatment arms. We also, as I said, tested those patient‑reported outcome measures, including fatigue and cognitive function. We did not see that there was a dramatic change within treatment arms, nor was there a substantial difference between the treatment arms.

And it's interesting, because I think that one of the reasons that we couldn't randomize is that there was such a concern that there would be a dramatic difference between these treatments. And at least in the patients who were included in each of these arms, there was not a dramatic difference, not for lack of testing. We tested these poor people—

Oliver Sartor: You tested, yeah.

Alicia Morgans: —but there was not a dramatic difference in the outcomes of those tests.

Oliver Sartor: Were you surprised?

Alicia Morgans: Absolutely. I would say that cognitive function is a really difficult construct to deconstruct. And there are multiple things that end up playing into one's cognitive function, including whether they might be depressed, or not sleeping well and really fatigued, or maybe they truly have some cognitive change over time. But to pull out each of these and to find differences can be really challenging.

And I think there's also this concept of the ceiling effect, which means that if someone has a really high cognitive function, they may actually have a decline in their function, but if our tests don't measure that high capacity, we're not able to find it.

So there are multiple reasons that this was the case. But it's also very possible, and really important, I think, that we may not have been testing the most vulnerable individuals who already have, perhaps, some mild cognitive change, and when exposed to some of these agents, do have more of an acceleration of that cognitive decline. Those patients might have been excluded from the study because you couldn't have dementia, even mild dementia, when you were getting into the study.

Oliver Sartor: That makes sense.

Alicia Morgans: So I think there may be multiple reasons we didn't find anything, but I was absolutely surprised.

Oliver Sartor: Yeah. Very interesting results, provocative results, outcome from PCF analysis. And I'm sure we're going to be hearing more, because in an abstract and some presentation here at ASCO GU, you can only cover so much at a time.

Alicia Morgans: True.

Oliver Sartor: So we look forward to hearing more. Anything else you'd like to cover about the study while we're still on UroToday?

Alicia Morgans: I would just say that I appreciate the patients and the investigators, including you and the team at Tulane, because it's hard to do these studies that don't involve the latest, greatest treatment. And the altruism of the patients and the time and investment of the investigators is just something that's so important in science, and truly, truly appreciated. But when we take this information back to our clinics, I think we can say there's no clear change in cognitive function, at least in this prospective study, at least in this one‑year time frame. So people can feel reassured, regardless of the treatment that they're on, that they're probably going to be OK.

And should they have complaints, should they have concerns, they should talk to their doctor about it. But there's nothing inherent and large about these treatments that's going to give them dementia or really cause cognitive decline, at least in this investigation.

Oliver Sartor: I think it's an important and positive message.

Alicia Morgans: Yes.

Oliver Sartor: Alicia, thank you so much for being on UroToday yet again, and thank you for your contributions to the field.

Alicia Morgans: Thank you so much.