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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, a good friend and colleague, Dr. Karim Fizazi, who is a Professor of Oncology and a GU Medical Oncologist at Gustave Roussy in Paris. Thank you so much for being here with me today, Karim.

Karim Fizazi: It's a pleasure, Alicia. Thank you for inviting me.

Alicia Morgans: Always. Well, I wanted to speak with you about some work that you and your team have done on a trial called the ODENZA trial. Really looking at darolutamide and in comparison to enzalutamide and trying to understand how different effects may be between these drugs.  And at ESMO, you recently presented some objective neurocognitive testing results that looked at this comparison. Can you tell us a little bit about that?

Karim Fizazi: Of course, yes. Thank you. So ODENZA is a prospective randomized trial with a primary endpoint of patient choice between darolutamide and enzalutamide. All these patients had mCRPC, metastatic castration-resistant disease, and they were randomized to receive one of these two drugs for three months. And then after this period of time, they were switched to receive the alternate agent, unless of course, they had experienced cancer progression. So that is, of course, in those cases, which were rare in the trial, they might, you know, go for something else like chemotherapy or an aberration. But generally speaking, the response rate was about 80%. So most patients of course carried on and received both periods of treatments. The primary endpoint, as I said, was to look at the preference between the two agents, and this was assessed by a questionnaire that patients filled out after the second period was over and before knowing whether they were responding or not.

Actually, what we reported at ASCO was that approximately 50% of men preferred darolutamide, 40% approximately preferred enzalutamide and 10% approximately had no real preference. So there was a trend for higher preference, favoring darolutamide, but this was not significant. So here at ESMO, we updated the analysis and we also looked at a secondary endpoint, a key secondary endpoint of this trial, which was the assessment of cognitive impairments from these agents. And I think this is very important because, for years, we suspect that enzalutamide is associated with cognitive impairments, at least in some patients, not in all. And to do that, we used the [inaudible 00:03:03] methodology was basically using tablets, patients can self-assess whenever they have cognitive impairment with the help of course, from someone from the team. And what we saw indeed varied statistically significant, and I think a clinically meaningful difference for some aspects of cognition and actually included verbal memory and also verbal learning.

So in other words, when patients are receiving darolutamide, they are more likely to better, basically act, or better think regarding how they can learn words and how they can remember things as compared to the same patients receiving enzalutamide. This was true for the first period, and this was also true in the overall period of time. So I think this is a true finding. And actually, it goes with what we were suspecting from these two agents in a context where darolutamide does not penetrate the blood-brain barrier while enzalutamide does. So this is another reason why we think that darolutamide is a quite safer drug with perhaps fewer side effects as compared to what we see sometimes with enzalutamide.

Alicia Morgans: I think that's so interesting, particularly because verbal learning and verbal memory are certain domains of a person's cognition that may explain why I have some patients wives say, "I tell him and he doesn't listen. And he doesn't remember." And that is absolutely oversimplifying those domains because they are certainly part of the executive function. If you can't take in data, you can't process it. And then you can't do what you need to do on the opposite end in terms of planning and achieving goals. But that is, I think very much reflective of some of the issues that come up in my clinic. What are your thoughts?

Karim Fizazi: I fully agree. I have really the same experience sometimes I see, especially in [inaudible 00:05:22], I see, a couple coming back to me when the patient has started on enzalutamide and the wife is actually concerned. She's telling me, "you know, he's just sitting down in his chair. He's just watching TV. He doesn't really speak anymore. Or when I'm speaking to him, he doesn't fully pay attention". Or as you said, he cannot really memorize what we've done or what we said. That's a minority, very clearly and enzalutamide remains a great drug, but for some patients, it's an issue. And I'm glad that we now have direct evidence that seems not to be the case or probably less with darolutamide.

Alicia Morgans: I would agree. And I also think it's fascinating as you said, that it is a minority of patients who seem to be heavily affected by these drugs, including enzalutamide, but it is a consideration if you are choosing a drug if you have a patient at risk or an elderly patient who may already have some early signs of mild cognitive change that choosing a drug that may not have this measurable effect, may be an option that is better for him. So I am very happy that there is some evidence of an option that there may be less of an effect there. So if you had to summarize your findings and give a message to clinicians who are thinking about treating these patients, what would that be?

Karim Fizazi: Well, I guess I would say that for the first time we have direct evidence that cognitive impairment is more seen at least for some aspects with enzalutamide as compared to darolutamide. And this is even more true when it comes to verbal learning and verbal memory. It's always good to have objective and direct evidence as compared to opinions or feelings that we of course have from all our clinics. I think this is important to counsel all the patients on, especially those elderly who are probably more at risk from suffering from these side effects of drugs.

Alicia Morgans: Well, thank you for gathering this evidence. And I really do look forward to hearing more from you and the ODENZA team, as things continue to develop, but congratulations on this work and for providing more guidance for us in our clinical care. We appreciate you, your patients, and all that you do.

Karim Fizazi: Thank you very much, Alicia.