Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist, and Associate Professor of Medicine at Northwestern University in Chicago, in the United States. I'm so thrilled to have here with me today, a friend and colleague, Dr. Karim Fizazi, who is a Professor of Oncology at Gustave Roussy in Paris, France. Thank you so much for being here with me today, Karim.

Karim Fizazi: Thank you very much, Alicia. It is a pleasure.

Alicia Morgans: Wonderful. Well, you know Karim, I wanted to speak with you a little bit about the ARAMIS trial and the overall survival data that you and the team presented in the New England Journal, fairly recently, just to talk about and really explore some of that data a little bit more in-depth. Are you able to remind us of what the study entailed?

Karim Fizazi:  Yes. Sure. So ARAMIS was really the first randomized Phase 3 trial for darolutamide, which is an androgen receptor antagonist, with different chemistry as compared to enzalutamide and apalutamide for example. So we first tested darolutamide in Phase 1 to advance the disease metastatic CRPC where obviously, we saw efficacy and a very nice pattern of toxicity, with no real side effect, we could tell that was related to the drug. When we designed the ARAMIS Phase 3 trial in men with the non-metastatic castration-resistant disease, in other words, a man with a rising PSA castration and a normal CT scan, a normal bone scan. So those men were randomized to keep on with androgen-deprivation therapy until they developed metastasis, and then, of course, they received treatment for metastatic CRPC. This was the control arm versus the experimental arm, which was ADT plus darolutamide.

A year ago, plus or minus, we reported the primary endpoint of metastasis-free survival, which was very clearly improved with an approximately 60% reduction in the risk of metastasis or death. And thus came together with a very safe pattern of toxicity, very very moderate toxicity as compared to the placebo, so this was just great. But as for SPARTAN or PROSPER, which are the two other big Phase 3 trials looking at next-generation, AR agents in the space, some people were still with some doubts about whether this was truly relevant to patients because, at the end of the day, you are looking at an image, not directly at the clinical benefit. So, this is why it was so important to carry on with a follow-up and to report the overall survival data. And this is what we just did in the paper some weeks ago, and obviously, that is really good news. We saw more than a 30% reduction in the risk of death with early intervention, with darolutamide as compared to another placebo.

And this happened in a context where more than half of the patients from the control arm had access to either a cross over of darolutamide or some other commercial AR access inhibitors like abiraterone or enzalutamide, etc on top of chemo, of course. Which means that it is probably really testing an early intervention that we're doing in this trial. The other good news is that the very nice signal, this very nice safety signal that we first saw a year ago, is confirmed with time. Basically, there is no big difference in terms of intellectual fatigue, for example, it's almost the same thing. We don't see memory impairment, we don't see excess in force, or in fractures, in hypertensions, all parameters and side effects that we sometimes see with other drugs that we are using in this space or in more advanced disease. So it is really great news for all the patients. And finally, on top of that, we saw some other glimpse, if you will, of efficacy, including pain control, quality of life is maintained, local symptoms, because some of these patients that have local progressions are prevented efficiently. So, I guess all the stories are really nice.

Alicia Morgans: I would completely agree. And I think it is so nice to have that confirmation that not just metastasis-free survival is actually prolonged, but actually overall survival. Because as you said, there were many patients who crossed over, who received darolutamide, or who received other life-prolonging agents. And I think it's really pretty compelling for us to see that it really is the earlier intervention with this intensified approach that is able to prolong life and that we really don't seem to be able to catch up with that early intervention, even if we start within a number of, say months, six months or even less, or so it seems to me, what would you say to that?

Karim Fizazi:  I fully agree with you and actually, it makes me think about what we just saw. Someone, two or three years ago, in another space of the disease, which is the metastatic castration-sensitive disease, with LATITUDE, STAMPEDE, and then ENZAMET and TITAN, where, actually the data are super consistent with, across the board, benefit with early intervention. Even in the two trials where we probably have the longest follow-up with [inaudible] now, LATITUDE and STAMPEDE. STAMPEDE was just presented at ESMO, again with an updated analysis. And we did the same a year ago with LATITUDE. So with longer follow-up and many more patients in the control arm, receiving, having access to salvage treatment, the curve has remained the same. The separation remains there. And actually what you are missing with not using your drug earlier is something you cannot catch up afterward, about... So, I think this is a very important demonstration.

Of course, it's not the final demonstration that early is better, but it is a very strong sign that we are seeing, I think, with these agents, trial after trial, almost every year we see a new trial and every year, it's the same story. And it actually makes sense. I mean, when you have a major oncogenic driver in cancer and you are hitting it hard. In a cancer that is aggressive, you are winning. If your hit is hard and early, and this is true, basically in other cancers that we saw, in whatever cancer that I can think about, this has been true in history. So I think prostate cancer is not an exception with best regards. And I think this is very important for us to remember for our patients.

Alicia Morgans: I think that is a great point, and really, to just emphasize that we can hit the cancer hard in this case, without hitting the person hard. Which I think is really an important distinction.  Because if we are able to hit that very sensitive driver on the cancer cell, we can really impair it and very clearly improve survival. But in this case, because of course, that driver is different in the cancer cell than it is in what is really going to affect the patient experience, we can at the same time, actually improve the patient's quality of life in some domains, or at least maintain it. So I think that is really important, and it is very clear, from this data and from the adverse event profile. The one final thing I would like to comment on is that I think it was really interesting, in this trial that patients who had had a seizure history, or who may have a higher risk of seizure were actually included in the trial. Can you, can you comment on that?

Karim Fizazi: There were indeed. And this is, again, in more contrast, with other trials where these patients were excluded. Those patients are not very frequent, but of course, you're always in trouble and that is true also in the metastatic CRPC setting, by the way, when you have a patient at risk. I saw in the past, some patients developing seizures on enzalutamide in the early development process of a drug, some almost 10 years ago now. That is not a good thing, of course.  And it could be, actually, a continued, seems to be a continuum of cognitive impairments and the worst is probably a seizure. And really saying that, with darolutamide, we really do not see an excess in seizures, an excess in cognitive impairment, except in falls, and fractures probably due to falls, is very reassuring to patients. Even if those side effects are not very frequent, they are very bad for patients, we all know it. It's great to see that we can prevent them from happening efficiently with that drug.

Alicia Morgans: Agree. So if you had to sum up this latest data, the final analysis for the trial, what would your message be?

Karim Fizazi: I think that besides the concept of non-metastatic castration-resistant disease, which is something some people are challenging and I can take the point, of course, because from the beginning, we know that the disease is somewhere. Until recently, only a biomarker PSA was able to tell us that something was happening, but nothing else, the patient was fine, it was asymptomatic mostly. And the imaging was normal by definition, but, we knew that the disease was somewhere. It's just the limit of the imaging that was challenged if you will.

So, nowadays we have next-generation hormone imagings with PET/PSMA, PET Choline, whole body MRI, these things. So, we can much better tell where the disease is located, in best setting where a bone scan and a CT scan are normal.  But still, the concern remains the same. The man remains the same at this time, point of time, the biology of the disease remains the same and the data is still applied to those men. So regardless of whether you have access and you are willing to use the next-generation imaging, all this data remains. I think this is something very important to remember, and it's just telling us that in, let's call it low burden CRPC, early treatment with these agents is better than deferred treatment. So I think this is the main message, regardless of whether you see, or won't see where the disease exactly is located.

Alicia Morgans: I completely agree. And just to emphasize, that when patients have negative conventional imaging, even if the PSMA PET or the Axumin^® PET or whatever type of PET you get is positive, that patient still fits the parameters of those patients included in this trial. And actually, we saw from some analysis that about 98% of the patients who fit these inclusion criteria will have a positive PET image. But just because they have a positive PET image, doesn't mean that the biology is somehow different, that they are different. And if they still fit those parameters, as I just defined, they still can benefit. And it is not just metastasis-free survival, it's overall survival.  So thank you so much for emphasizing that. And thank you so much for your work and for your time today. I really appreciate it.

Karim Fizazi:  Thank you, Alicia.