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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm pleased to be joined by Dr. Fred Saad, who's a professor at the University of Montreal, well-known to all of our UroToday listeners. And we're delighted to have a conversation today around the recent ARASENS data. As we know, ARASENS has been transformative over the last 12 to 18 months, and we're seeing some additional analyses come out over the last few months as well. And certainly, this discussion today around PSA response, these rapid, deep, and durable PSA responses that we're seeing and some of the data presented by Dr. Saad at the AUA and some updates coming as well in future meetings. So welcome, Dr. Saad. It's great to have you.

Fred Saad: Always fun.

Zach Klaassen: So let's just jump in. So previous work, we've seen this in some other analyses from other trials. This rapid and quick and durable response, from a PSA standpoint, results in excellent outcomes. From your standpoint, whether this is biologically, how are we seeing this and what does this mean for the patients?

Fred Saad: Yeah, so in general, you're right. I mean, we've known that the response to PSA, and especially PSA nadir, closely correlates with outcome in terms of progression-free survival, but more importantly even overall survival. And this is all the way back when we were using ADT for metastatic disease. But what's nice is that this is holding up even now in the era of intensification.

Zach Klaassen: Right.

Fred Saad: And so with novel hormonal therapies or ARPIs, whatever we call them, we see that we can do better than ADT alone. And this is really important because it does correlate to better outcomes. So patients and us, psychologically, like to see PSA go down, but there's actually a biological importance in this decline in PSA.

Zach Klaassen: And one of the nice things about the ARASENS trial, and I know our listeners and certainly yourself understand that this control, it was a very clean trial, great control arm, ADT plus docetaxel. And so even among an excellent control arm with the triplet therapy, two-thirds of these patients had a PSA 90 response at 12 weeks compared to 43% in that control arm. So in your opinion, is darolutamide responsible for that extra 20% improvement? Or what're your thoughts on that really deep PSA 90 response we're seeing in the triplet?

Fred Saad: Oh, clearly, the darolutamide is responsible because, like you said, what's nice about the ARASENS trial is it was planned ahead of time to address the point of, what is the value of triplet therapy compared to a strong control arm of doublet therapy. And at the time we designed ARASENS, the doublet therapy that was considered the worldwide standard of care was ADT and docetaxel.

Zach Klaassen: Right.

Fred Saad: And so we took that, and we said, how can we build on that? And it was a successful trial all across. We delayed castration resistance, significantly improved overall survival, and now we're trying to figure out other parameters to help us for future trials. And one of them is how deep we can get the PSA response.

Zach Klaassen: No, absolutely. And I think you mentioned all these secondary endpoints that we're seeing some of the nuances, what we're talking about today from these additional analyses, and one of those we'll hit on too is this undetectable PSA at 24 weeks, 36 weeks. And as you mentioned off the top, leading to increased time to PSA reduction resulting in improvements in overall survival. So we're seeing not only that that undetectable rate is important, psychologically, from the clinician and the patient standpoint, but also resulting in improved overall survival outcomes too.

Fred Saad: Yes.

Zach Klaassen: So as you mentioned, because of that, this triplet therapy thought process is hitting it hard upfront and clearly those undetectable rates are leading to more outcomes. Is this your rationale too? If we can get a really good response upfront, whether it's a triplet therapy or whatever we decide over the next five years, that's leading to the survival benefits?

Fred Saad: Absolutely. And I think the new trials are all using this as an early surrogate that we're going in the right direction. And so we know that some patients with ADT alone will get to undetectable PSA, but it's only about 10% to 12%, 15%. You add chemotherapy to it, and we now know with a prospective study looking at this, less than 25% are getting to undetectable.

Zach Klaassen: Right.

Fred Saad: Then you add darolutamide, and now we're almost 70%. So we more than double, almost triple, the likelihood of getting to that holy grail that's less than 0.2. And like you said, that is tremendous. I mean, we're improving or reducing the risk of death by two-thirds if we can get to undetectable versus simply not getting to undetectable. So really, when I talk to patients and they're thrilled about having their PSA go down 50%, that's good, but that's far from what we're aiming for. I tell them we're aiming for zero. We're aiming for undetectable, and that's what we need to do in the clinical trials. And whether it's triplet, quadruple, we really need to get to that level because it delays the need for subsequent therapy and really gives us a hope that patients will have time to die of something else.

Zach Klaassen: That's right. And you actually kind of elegantly answered part of my next question, which was how do you present this data to the patients? And you said, in your clinic, a guy has a PSA of 85, 55 years old, great health. Are you talking about these PSA targets in that first conversation? Or how are you presenting the entirety of ARASENS to these folks?

Fred Saad: Yeah, absolutely. I tell them that we can almost triple the likelihood of getting them to that level that we hope to get with our surgical techniques, right?

Zach Klaassen: Yeah, that's right.

Fred Saad: We're aiming to have no viable cancer. And if we can get to that point, it doesn't mean we've cured them, but we've delayed the recurrence. And so patients understand this, that this is what we're going to work really hard to do. And fortunately, more than two-thirds we can get there.

Zach Klaassen: Yeah.

Fred Saad: So the question is, what do we do with that one-third that we don't get there is really the question of new clinical trials of how we can build on these successes of getting to that level. And the likelihood of getting to that level is that we can keep at that level for much, much longer and not have to think about subsequent therapies and the more difficult questions, which actually leads to the death of these patients.

Zach Klaassen: Right. So let's talk about that one-third. So you have two-thirds of an excellent response. Those are the easy ones. So that one-third, are you trying other therapies? Are those candidates for those next clinical trials? How are you taking that one-third of patients? How are you counseling them?

Fred Saad: Yeah. So how we're counseling them, first, for us as clinicians, not everybody's going to have a clinical trial available.

Zach Klaassen: Sure.

Fred Saad: But clearly, if a patient doesn't get to at least 90% or ideally below 0.2, that should signal how you follow patients.

Zach Klaassen: Right.

Fred Saad: So I will follow them more intently. And on the flip side, if somebody gets to below 0.2, I can say, well, we can spread out our visits, we can spread out the imaging. So I think we have to learn to personalize. We can't put everybody in the same recipe.

Zach Klaassen: That's right.

Fred Saad: So if a patient gets to below 0.2, I spread out. If he doesn't, then I'm going to watch them every couple of months, every three months, to try to get a signal for early recurrence that I can act on. Now, whether treating the prostate, because a lot of these patients didn't get treatment in the prostate, will that help us to get down? That's what we need to work on and clinical trials are looking at. And biologically rational next or additional therapies, whether they harbor a BRCA mutation, whether they have some other anomalies that we can act on, is, I think, the way our future trials are going, not waiting for them to have multiple new metastases, but act on the early signals that we might need to do better.

Zach Klaassen: Yeah, absolutely. Anything from your data that we haven't discussed that you'd like to share with the audience today?

Fred Saad: Well, I think there's going to be more data that's interesting coming up at ESMO, hopefully. But there's data looking at the question of well, do the low-volume or low-risk patients actually need the added chemotherapy?

Zach Klaassen: Right.

Fred Saad: Well, I'm going to present some data that's absolutely outstanding in how low and what percentage get to this undetectable. It's absolutely outstanding. So it goes back to the concept that I've been pushing for many years that patients that are likely to suffer from the disease and that includes the low volume, low risk, those patients also deserve to be hit hard.

Zach Klaassen: Yes.

Fred Saad: And maybe we can start hoping that we might actually be able to stop therapy after two or three years.

Zach Klaassen: Right.

Fred Saad: We're complete remission. The hope of hitting hard is that we can actually maybe stop and not have every patient castrate for the rest of their lives. And I think that's where we need to go, intensification, but can we find patients we can start deintensifying and leaving them alone after some time?

Zach Klaassen: Well, I think, too, it's a good point to just hit with our viewers that it's triple therapy, but it's a finite time of docetaxel. This is a six course, and then they go on to their darolutamide. And in the trial, the patients were on darolutamide for up to four years. Right? So it is triplet, but then it quickly comes back to doublet after that initial sort of six cycles of docetaxel. So I think you're absolutely right. I think if we can get that person with a PSA of 25, low-volume disease or low-risk disease, hit them hard, de-escalate, and at that point start to think about cures in these patients, I think this is fascinating. I look forward to seeing your data at ESMO. And obviously, it's just around the corner, too. Dr. Saad, fantastic discussion, as always, and we really appreciate your time today.

Fred Saad: Thanks for having me. And it's really great to be able to use that four-letter word in metastatic disease.

Zach Klaassen: What's that?

Fred Saad: That C-U-R-E.

Zach Klaassen: You're right.

Fred Saad: The cure. We never thought we would use it in my lifetime, and I think we can start hoping to use that word.

Zach Klaassen: Absolutely. Thanks so much, Dr. Saad.

Fred Saad: Take care.