Alicia Morgans: So wonderful to be here. Thanks so much, Zach.
Zachary Klaassen: ARACOG is something we've been looking at for a long time and hearing results in the trials in progress. When you and I see these patients, cognitive dysfunction is a huge part of how we think about how we're going to escalate, what agents we're going to use. What was the genesis to look at these two agents head-to-head?
Alicia Morgans: Well, I think this was inspired actually, of course, by a patient. Many years ago, I saw a patient in early days when we really had only abiraterone and enzalutamide. I had a patient with enzalutamide who was particularly affected or seemed so by the penetration of enzalutamide into the CNS through the blood-brain barrier. We were able to stop the agent and that patient had a recovery of symptoms that he was feeling at the time. One patient is not going to make or break anybody's decision-making around enzalutamide or any other drug, and I use the drug all the time for patients, but it seemed like there might be a particular vulnerability for this individual and the possibility that crossing the blood-brain barrier and having this androgen receptor antagonist activity in the CNS may be a signal, may cause an effect that would be important to patients.
Many years ago we were able to apply to the Prostate Cancer Foundation and get a challenge award around randomizing patients to receive either darolutamide or enzalutamide. We specifically designed the trial around a primary endpoint that was a cognitive endpoint. This was so important because when you have a primary endpoint focused on something like that, you can put your energy and the power of the statistics into really analyzing that particular thing rather than having it be an afterthought or simply just an adverse event that we're collecting. This was, I think, one of the most important pieces. We randomized specifically between enzalutamide and darolutamide, because darolutamide doesn't have the penetration, at least in preclinical models, into the CNS through the blood-brain barrier. This is why we designed it that way. Of course, as I said, primary endpoint was a cognitive change, but we also included in addition to computer-based cognitive testing, patient-reported outcome measures, as well as assessments of function and an analysis of adverse events as they are also collected within the study.
Zachary Klaassen: That's great because I think we know both these agents work, right? It's just a matter of designing it. That's an important point. I'm glad you laid that out. Just go through some of the trial design and specifically when these tools were assessed, when the data was collected.
Alicia Morgans: Sure. It was basically collected from 2021 until 2024. Well, that's when patients enrolled, and we've been collecting data even through 2026. We really were able, I think, with all of that really rigorous collection to make sure that we captured a whole 48 weeks or basically a year in clinical trial terms of follow-up for our patients.
Zachary Klaassen: That's great. Let's get to the good part. What were the results that you found from the study?
Alicia Morgans: Sure. The primary endpoint was maximally changed cognitive domain. This is a new construct, at least in the prostate cancer world. This is something that's been around in behavioral health for many years essentially. But we decided that we wanted to look at a patient's cognitive change from their baseline computer-based testing as an objective measure of how their cognitive function may change over time and we made the primary endpoint time point at 24 weeks, so six months into their treatment. Throughout this treatment, at 12 weeks and at 24 weeks, if patients experienced more extreme cognitive change on their computer-based testing or on their patient-reported outcome testing, or if they had a fall or a major neurologic adverse event. They could cross from one arm to the other. Patients who did cross before 28 weeks had their cognitive testing score from that earlier time point incorporated into the 24-week time point.
It was really important for us to include change from baseline because everyone starts at a different level. We were also including some patients who had metastatic hormone-sensitive disease really earlier on in their ADT treatment, as well as some patients who had mCRPC or non-metastatic CRPC. They had been exposed to ADT for a long period of time making it important, again, that we started everybody from a fresh baseline.
The primary endpoint suggested that there was a significantly greater change in that maximally changed cognitive domain for patients who were treated with enzalutamide than for darolutamide. The domains themselves were actually different too. This I really want to make sure I explain, because the maximally changed cognitive domain was specifically set to be defined for each treatment arm, because we wanted to take the worst of the worst score and compare it between drugs to make sure that we weren't going to miss some difference should it exist.
Besides that, when we measure cognitive function, we know that there's overlap in cognitive abilities in these individual computer-based tests and it's not as easy as measuring just a single PSA blood test. We wanted to make sure that we captured that overlap. Between the worst domain for enzalutamide and the worst domain for darolutamide, there was a significantly greater change in those patients treated with enzalutamide.
Zachary Klaassen: It's a great summary of not complicated results, but just the nuances. You explained that really nicely. When we look at ASCO data, we're always thinking, what can we take to our clinic tomorrow? This seems like data that we can counsel our patients tomorrow when we're thinking about choosing an ARPI. How are you going to use this data in your clinic when you go back to work?
Alicia Morgans: Well, I think importantly, enzalutamide and darolutamide are similarly both ARPIs, but they don't necessarily have exact overlap in their indications. There are places where we have the opportunity to use enzalutamide actually across the spectrum where we wouldn't use darolutamide. We're very fortunate to have that opportunity in non-metastatic hormone-sensitive disease as well as mCRPC. Still, of course, prioritizing that agent there, maybe watching patients closely, which we already do and making sure that if they have cognitive change, we talk to them about steps to reduce or reverse that burden. But when we do have overlap and opportunity in the non-metastatic CRPC setting or in metastatic hormone-sensitive disease, we, I think, should think about this particular issue as something that might be included in a shared decision. For patients who are particularly vulnerable, or if a patient's on enzalutamide and has a cognitive change, we might have an opportunity with darolutamide as a different agent to perhaps either reverse that change or avoid that change if that is of high priority and the patient is particularly vulnerable to change.
Zachary Klaassen: That's great. Anything we haven't hit on from ARACOG? Any take-home messages for our listeners?
Alicia Morgans: Well, I think if people are looking at other coverage or reading the abstract, they may see some information about crossover. As I said, patients had that opportunity to cross over during treatment, and patients only crossover from enzalutamide to darolutamide. In this study, they did not cross from darolutamide to enzalutamide. I think that can be considered extremely striking and is important was a measurable pre-specified secondary endpoint. But I think it's important to understand that darolutamide was provided free of charge for the study patients. Enzalutamide had to be obtained through insurance coverage.
We actually made a patient could only be eligible if they had that pharmacy review of their benefits and had a copayment that was going to be reasonable and acceptable to the individual. Before they enrolled, they had to have that opportunity and ability, but still there is a financial toxicity difference there. I think that that may be something that was associated perhaps with the crossover rate. It's also really possible that patients who had that greater cognitive change were more bothered by the cognitive change and also decided to crossover for that reason. But I think it's important to unpack that and not think that this was a completely unidirectional decision-making without some other potential underlying cause.
Zachary Klaassen: That's a great clarification. Congratulations on a great trial here. This has been a huge lift over the last several years, and it's great to see the data. Thanks for joining us, Alicia.
Alicia Morgans: Thank you so much, Zach.