Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so pleased to have here with me today a friend and colleague, Dr. Fred Saad, who's a Professor and Chief of Urology at the University Of Montreal Hospital Center in Montreal, Canada. Thank you so much for being here with me today, Fred.

Fred Saad: My pleasure, Alicia.

Alicia Morgans: Wonderful. I wanted to pick your brain a little bit about the ARAMIS trial, which was a trial of men with non-metastatic castration-resistant prostate cancer, who were ultimately randomized to ADT, with or without darolutamide. We recently heard that this trial demonstrated an overall survival benefit in the population. I'd like to hear your thoughts on this data, on the MFS, or metastasis-free survival, data that came before, and then certainly the importance of the overall survival data as well.

Fred Saad: Right. I think many of us and our patients especially were saying, "How could we not do anything in a patient who's got a rising PSA, who's castrate, and tell them we have to wait until you become metastatic before we can treat you?" If we know they're going to become metastatic, especially with rapidly rising PSA that'll make them high-risk. These trials, ARAMIS especially, and SPARTAN and PROSPER, all dealt with an extremely effective agent against the androgen receptor. As reported in the New England Journal for all three and ARAMIS reported very strong MFS, metastasis-free survival, of about 22 months delaying, which was in itself extremely impressive and got approval based on that.

Obviously there are some people that wondered, to what extent is metastasis-free survival important? Does that really translate to a better overall survival? Or is it just a stage migration, and we're just giving a longer amount of therapy to end up with the same result at the end of the day, if people are treated well when they become metastatic? This overall survival data is extremely important. I think and I hope it's going to shut the door on the idea that treating early CRPC doesn't really benefit the patient. It absolutely does.

And we had the impression, or already did, in the metastatic setting when patients were low volume metastatic, they seemed to do much better and responded much longer than the patients that were more heavily burdened by metastasis. This, I think, is confirming what we all hope would be the case.

Alicia Morgans: I think that, as you alluded to, it's almost surprising in a way, so not surprising that one of these agents seem to meet overall survival, so that they all have, because as you mentioned, these are all androgen receptor directed therapies, they're all AR antagonists and similar in some ways. But the fact that these patients were relatively early on in their castration-resistant disease state, and then still had a survival benefit, despite subsequent therapies, I think was potentially surprising as we think about all of the things that we know prolong life, that they could have received over the course of their disease treatment.

Fred Saad: Absolutely. I had the honor or the misfortune of being the PI on arterenol. How many people remember the word arterenol? It was the third novel androgen therapy. And just because there were abiraterone and enzalutamide, we weren't able to show an overall survival advantage in the metastatic CRPC state because we were able to compensate with good therapies. When you think about that, these patients, or even earlier, we had so much more opportunity to contaminate the placebo arm because people were treated early or followed very intensely, and we still end up with amazing differences.

We're not talking two or three months differences. These are going to be reported and we're talking much better overall survival improvements, even though we had all these opportunities. Really, starting early really makes a difference for patients in terms of delaying metastasis, but improving overall survival.

Alicia Morgans: I think, like you said, it is impressive. The hazard ratio for the survival benefit in ARAMIS was 0.69, highly statistically significant, 0.003. As you said, this is not just a 0.75, 0.8. This is really a significant and clear benefit in terms of survival, despite subsequent therapy.

Also, what are your thoughts on darolutamide as an agent? I'm sure you've had experience with enzalutamide, apalutamide, and darolutamide. There's no need to compare the three because certainly none of the studies have compared to three, but on its own, how has this drug fared in your practice?

Fred Saad: So far, it's been really quite impressive. I think I always caution about an individual practice. We can have good or bad experiences, but when you look at the data, there are very little differences with the placebo arm. It's very reassuring. It was developed to have a drug that goes into the brain less. The results seem to be really quite spectacular when you think about the differences in adverse events between the placebo and the treated patients, there were very, very little differences. Patients tolerate it very well.

As well as tolerating it well, the improvement in overall survival, delaying metastasis, but also importantly, what's going to be reported at ASCO is delaying the pain, which was very significant, delaying SSEs that come with metastatic disease, and delaying the need for chemotherapy. So really, meeting all its endpoints, I think, encourages people to take this entity seriously. For many, many years, the FDA and others really didn't take... They said we created an entity that we're now wanting to treat. I think this entity really needs to be considered a very lethal and very morbid entity and to treat it early makes a huge difference for patients.

Alicia Morgans: I agree. And thankfully, the FDA seems to agree at this point as well. Now, we thankfully have access to this therapy. As you're treating this disease state, non-metastatic castration-resistant prostate cancer, the million dollar question that I asked many people, and I'm sure you've thought about, is how this disease state that we've created is actually affected by the evolving imaging landscape? What are your thoughts there and how do you think the changes that we're seeing in our ability to image disease that's less burdensome with some of these molecular tracers will affect peoples' thoughts about the non-metastatic CRPC setting and the use of agents like darolutamide?

Fred Saad: This question comes up a lot and I think we all agree. Anybody who treats this entity recognizes a rapidly rising PSA is metastatic somewhere. It's just that our technology doesn't allow us to see it. Now we have technology that allows us to see it. And we have data that says that probably 95% of patients, if we looked strong enough, will have something. The bottom line is, does it change the way we should manage it? And the answer is no.

The biology of this disease with rapidly rising PSA is it needs systemic therapy. If you're going to do imaging, it's because you're going to act on it. If you do see one or two lesions and you irradiate them, what's the likelihood you're going to help the patient? Probably zero. In patients with a rapidly rising PSA, a biology that's aggressive needs systemic therapy and needs to have the kind of therapy that darolutamide offers and the other AR antagonists.

On the other hand, if a patient has a very slow rising PSA, then I think there's a place for novel imaging, like PSMA, because if you do have a solitary lesion in a slowly rising PSA, maybe there is an opportunity to target it with focal intensive therapy. I think the biology needs to dictate what we're going to need in terms of imaging and what we're going to need in terms of treatment. I wouldn't waste. We don't do PSMA in those kinds of patients because we feel it's an unreasonable use of resources since at the end of the day, it's going to be the same treatment.

Alicia Morgans: I have to agree with you. I think that's a really pragmatic approach. Obviously we all learned in medical school, we don't do a test unless we have already planned what we're going to do with the outcome of the test, whether it's positive, negative, or somewhere in between. If we know already that we have an agent that can treat the patient and we don't really have other options for focal therapy, particularly in the rapidly rising PSA, PSA doubling time it's really short, that it doesn't make sense to do the imaging in that setting. You already have a treatment that's specifically designed to take care of that. So, very, very pragmatic, and I completely agree.

As you think about the overall survival data from ARAMIS, what would your take-home message be for darolutamide and the other agents that treat patients with non-metastatic CRPC?

Fred Saad: I think what's important is that physicians that take care of these patients recognize this entity is important, that we have got effective therapies. And fortunately, the effective therapies have shown, and darolutamide definitely has shown that we don't diminish quality of life by treating these patients because our first obligation is to do no harm. So if we're not going to harm a patient's quality of life, because they feel perfectly fine in this state, they wonder why we're treating them in some cases. We need to explain that this is going to delay the progression and improve their survival while maintaining their quality of life, which is I think what all the patients hope to get when they come to see us.

Alicia Morgans: I completely agree. We didn't even get into it, but the quality of life data that was presented, maybe it was a few months ago, maybe not quite a year ago by Karim Fizazi suggested that patients actually had improved quality of life as it relates to bowel and bladder complaints. Maintenance of quality of life, improvements in quality of life, that plus prolongation of life is really all we can ask for until we finally find a cure for this disease. I agree with all that you've said, and I appreciate you taking the time to talk through the ARAMIS trial with me today. Thank you.

Fred Saad: It's a pleasure.