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Alicia Morgans: Hi, I'm thrilled to have here with me today, Dr. Fred Saad, who is the professor and chairman of Urology at the University of Montreal. Thank you so much for joining me today.

Fred Saad: It's always a pleasure.

Alicia Morgans: Wonderful. So, I wanted to talk to you a little bit about Darolutamide. You've been involved in some of the large trials with this medication, including the ARAMIS trial, and we just heard at ASCO some updated data from the ARAMIS trial.

Can you tell us a little bit about the trial design, just to remind everybody of the population and what was tested, and then some of the updated findings?

Fred Saad: Right. So, Darolutamide was tested in a non-metastatic or M0 castration resistant population of patients who had high-risk features. So, PSA doubling time of less than 10 months, no evidence of metastasis on conventional imaging, because some patients in France and other European countries did get PSMAs. And if they were positive on PSMA but negative on conventional, they were still allowed to be part of the study if the investigator felt comfortable. And these patients were put on to Darolutamide or a placebo on top of their continuous ADT, which is important because sometimes people think, "Oh, it's a hormonal therapy. We can stop the ADT." Every single phase three trial always continued the ADT, including this one.

So very similar to SPARTAN and PROSPER, with a primary endpoint of metastasis free survival, which was clearly met; almost two years improvement and metastasis free survival. So, going from non-visible mets because we all considered, they're probably micrometastatic at that state, to visible mets on imaging. Almost two-year improvement over patients who were not treated with Darolutamide.

So, this was repeated in this meeting at ASCO, but with a bit of a focus on the quality of life. And you know, this was a metastasis free survival study, but we forget that patients can progress symptomatically, can run into issues with local progression of the disease, which would not be part of the metastasis free survival endpoint. And they show clearly that these patients benefited from Darolutamide in terms of urinary and bowel symptoms compared to patients who weren't on Darolutamide.

Alicia Morgans: So, that was something that I thought was really interesting. These are patients who had primarily had, for the most part I think, local treatment, definitive therapy for their localized prostate cancer, if they had this biochemical recurrence, they must have had some local therapy or we would presume they did, so prostatectomy or radiation. And then, it was really interesting to me that there were symptoms from those local type, or what I would imagine would be local symptoms or complications of the radiation if we're talking about bowel, and Darolutamide was actually helpful in reducing that symptom burden as compared to ADT alone. It was a little bit counterintuitive to me and I just thought that was an interesting finding.

Fred Saad: So, you clearly work in a large center of excellence-

Alicia Morgans: That's kind of you. Yes, thank you-

Fred Saad: ... because you assumed that patients got local therapy. In the real world, a lot of patients who have high risk, high volume disease don't get local therapy. You have to remember, these patients were treated years before coming onto the study. They had ADT became castration resistant, and then put into the study. And there was an era where a lot of patients with high-risk features, it was felt that why harm them with surgery or radiation? Why not just give them ADT and control their disease and avoid the complications?

And it's really only a few years ago that we realized that adding local therapy to ADT actually improves overall survival, delays castration resistance. So now, I would agree 100% that patients who go untreated with localized disease would be almost unheard of, but it still happens. So these patients who don't have good local control-

Alicia Morgans: That makes sense then-

Fred Saad: ... will progress, go into retention bleed, and you know, we treat these patients who, for whatever reason, didn't get any local treatment then maybe they presented with metastatic disease, and then became castration, and the local issues become a real problem.

Alicia Morgans: Absolutely. So it's interesting, so these were maybe some primary ADT type patients, or-

Fred Saad: Yeah, and even radiation patients who got suboptimal doses of radiation, right?

Alicia Morgans: Absolutely.

Fred Saad: I mean, we used to give 63, 64 grade, which was pretty benign radiation. And when you do PSMA testing, it lights up in the prostate even though they got so-called radiation. And so, I think we think of the metastasis and what's so important about metastasis, but for the patient's symptoms, local control with this kind of systemic therapies are, I think, critically important.

Alicia Morgans: Absolutely. And it was interesting that it must have been important because these were the domains in which we actually saw some benefit. So, there must have been some difference. And we also have to remember that a large proportion of these patients were actually enrolled internationally, not necessarily from North America where you and I practice. So, that's really interesting, and I think something that we could ... it's important to make sure that listeners know because this is a little bit of a different patient population, and included those patients who didn't necessarily get surgery, or optimal radiation to the local disease. So thank you for clarifying that.

Fred Saad: Yeah. And you know, if patients become metastatic and we see it on imaging, we ethically wouldn't let them progress to symptomatic metastatic disease. But locally, they still didn't meet the MFS endpoint, so they were allowed to stay on the placebo and-

Alicia Morgans: Yes, and develop 

Fred Saad: ... continue to progress, go into retention bleeds.

So, it is a big problem for us in urology because we have to deal with these local issues that sometimes override the metastatic issues that occur. So we have to think of the patient as a whole.

Alicia Morgans: So, when people talk about non metastatic CRPC or M0 CRPC not necessarily being something that's worth treating, I think particularly in this patient population, we're demonstrating that adding the systemic therapy may actually reduce these local complications, and may be of substantial benefit to those patients, which was demonstrated in this study.

So, really carves out a niche of patients who among others, may actually have even in the context of people who say it's not worth treating this patient population, may have some issues that are worth treating.

Fred Saad: I agree 100%. I think there are multiple good reasons for taking these high-risk patients. Rapid doubling times that are destined to become metastatic or suffer from all sorts of complications of their disease. Totally different than the patient with a very slow rising PSA, who's non metastatic CRPC, where with this novel imaging of PSMA, might be an opportunity to actually look and find where that disease is, and attack it with local intensive therapy. But otherwise, rapidly rising PSA is bad biology, needs systemic therapy, both for the local disease and for the systemic diseases.

Alicia Morgans: Very important. So, thank you for bringing all of that to light. That's really actually ... it's really useful and it's not something I think we've talked about on here before. So, really helpful information as we think of making these clinical choices.

And you know, I'd love to hear where Darolutamide's going next because there are some ongoing trials. I know we've participated in the ARASENS trial. Can you tell us a little bit about that study?

Fred Saad: Yeah. So, ARASENS is another area that Darolutamide is being tested in. And so, ARASENS is really taking the next logical step in metastatic hormone sensitive prostate cancer. We know that docetaxel helps, tremendous response and improvement overall survival, abiraterone clearly very beneficial. The question is, should we put them together?

And so, ARASENS is asking the question in patients getting Docetaxel, so everybody in ARASENS is getting ADT plus Docetaxel, plus or minus Darolutamide to really answer, is the triplet better than the doublet? Should we give everything to attack all the different clones of prostate cancer, and maybe aim for even much better improvements than going the sequential route, which would be a logical choice in patients who start with chemo, then go onto a hormonal agent.

But in the real world, what often happens is people wait, and wait, and then these hormonal therapies are actually much more beneficial if you can give them with low volume disease. You miss windows of opportunity when you don't start upfront in those high-risk patients. So, hopefully, ARASENS is going to answer that question and help us to better treat these patients.

Alicia Morgans: I think ARASENS is designed to answer that question, which is critically important, because we've been talking a lot at ASCO about that question, and we don't have a study actually designed to answer it.

So for example, ENZAMET, which you know is now new data coming out, is really looking at the metastatic hormone sensitive population and a majority of patients, just over half actually, in both of these arms actually received docetaxel, and then either nilutamide, flutamide, bicalutamide with their ADT or Enzalutamide with their ADT. And we saw in this, that it was not necessarily clear that there was a benefit from the triplet therapy, but the study is not actually designed to answer that question clearly. And there's a different control arm here. If we have this active bicalutamide, nilutamide, flutamide.

So, I think ARASENS is something that is much cleaner and will answer that question because it is designed to answer that question, powered to answer that question. So I think we all are looking forward to that. And when do you expect that we will start to have some early data from ARASENS?

Fred Saad: Yeah, well it's an overall survival primary endpoint. Really, that is the holy grail. We need to be aiming not only to delay progression, but actually to improve overall survival. But these are relatively high risk, high volume patients that went in because you have to ethically ... and you needed to to give docetaxel to all these patients.

So, my prediction is we might start getting data within a year because these patients, especially if they're getting only docetaxel, don't do so great for very long. And so, I think we really need to attack these patients earlier, more efficiently. The next phase of research hopefully is going to help us to decide should we be personalized even more? Should we understand what we're treating in these patients that come in with a lot of metastatic burdens? Probably clones might require PARP inhibition, might even benefit from immunotherapy.

The field is really growing and I think we're trying to understand what we're actually treating, rather than just on imaging saying, "This number of mets is high volume, that number is low volume." I think we need to go to the next level.

Alicia Morgans: Well, I completely agree, and I really appreciate you talking through these advances and these questions with this new drug that we're thinking about using in the future, should we see that it's available to us. And I hope that sometime either, around ASCO next year or perhaps a little bit later, we are able to hear some of the early results that are coming out of ARASENS and continued to learn more about this option for potentially treating prostate cancer. So thank you so much for your time today.

Fred Saad: It's a pleasure and thanks for the opportunity.