Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, Dr. Karim Fizazi, who is the Professor of Oncology and a GU medical oncologist at Gustave Roussy in Paris, France. Thank you so much for being here with us today, Karim.

Karim Fizazi: Thank you, Alicia. Thank you very much.

Alicia Morgans: Wonderful. Well, I wanted to speak with you about an exciting ASCO 2020 Virtual Meeting presentation that you've given and a very exciting co-publication in the New England Journal of Medicine on the PROSPER study, which looked at enzalutamide in patients who had non-metastatic castration-resistant prostate cancer, previously reported to improve metastasis-free survival. And now you have exciting new results that you shared with us at ASCO and in the New England Journal. Can you tell us a little bit more about that?

Karim Fizazi: Sure. So PROSPER is a Phase III trial looking at enzalutamide, as you said, in men with non-metastatic castration-resistant disease. So in other words, patients experiencing a PSA rise while on androgen deprivation therapy, regardless of whether they have been treated locally or not for that prostate cancer when it was localized. And as you said, we already know that enzalutamide is a patent drug to postpone the time to metastasis or death. [inaudible] of primary endpoint was met, and that was reported already two years ago with approximately a 70% reduction in the risk, which is by itself, very big. We have a longer follow-up now. We have data mature enough to look at overall survival. And indeed, we could show that overall survival is significantly improved favoring the enzalutamide arm.

We observed a 27% reduction in the risk of death and the medians actually have been reached. So it's about 67 a month now with enzalutamide, as opposed to 56. Approximately a year of additional life, favoring enzalutamide, which is really big for such a population of elderly men. And this is in a context where the majority of men in the placebo arm could actually have access to an active drug when they progressed. Approximately two-thirds of them received a life-prolonging agent, which obviously did not help the early enzalutamide arm.

So I think this is very important, not only a time to... Metastasis is postponed. And this is, as we all know as a medical oncologist, often synonymous to time to symptoms, but also our overall survival is prolonged with early enzalutamide, which to me means that this family of drugs truly becomes the standard of care for these men.

Alicia Morgans: Absolutely. I think it's really exciting, actually, wonderful to think about a median survival that is over five years for these patients who are castration-resistant. That's a very vulnerable time for patients when things are progressing, and to provide an additional year of survival for that patient population, and to be able to encourage them that time is still on their side to a large extent, particularly in such an elderly population, I think is such an important contribution. And I think what's also important PROSPER is that the safety profile actually still appeared consistent with what we already know in terms of enzalutamide. Can you talk a little bit about that?

Karim Fizazi: Sure. Yes, no real new signal, but really confirmation regarding what we knew from enzalutamide in both of the metastatic CRPC, the castration metastatic sensitive setting, and also the N0 CRPC setting with the earlier analysis that was shown. So basically [inaudible] penetrates the blood-brain barrier, and it seems that part of the safety profile is associated with that. So we do see an excess in fatigue, or in force, or sometimes difficulties for patients to concentrate. So this is important to know and to take into account when starting this agent. Sometimes when I have to prescribe enzalutamide in the metastatic CRPC setting in an older patient, I tend to dose reduce to try to avoid the side-effects because this is, I think, something important. Also, and maybe in contradiction to what we thought maybe 10 years ago, hypertension seems to be also clearly a side-effect related to enzalutamide.

And actually we have more and more data regarding that. There was a presentation at ASCO GU for example regarding this, to try to tease out why we see this side effect. Practically speaking, I think it's important for physicians to know it and to measure blood pressure, to treat their patients, or to do this together with a GP, so that we can avoid the consequences of hypertension. But generally speaking, this is a drug that can be handled, again, monitoring is needed, but again, no new signal, with a longer exposure to this agent, invest longterm analysis.

Alicia Morgans: Excellent. And in terms of the patient-reported data, it seems like patients also tolerated this treatment very well. Can you speak to that as well?

Karim Fizazi: Right. Quality of life data have been reported last year I think, so basically, as you said, quality of life was maintained. So even though we see some side effects with enzalutamide, they are counterbalanced by cancer progression rates, same terms, and we don't see a detrimental quality of life with enzalutamide which is very reassuring. Also what was shown with this longterm analysis, is that time to the use of a cytotoxic is very clearly postponed with the early use of enzalutamide, which has important consequences for patients, of course, because if we're talking about a chemotherapy agent, some patients obviously don't want to receive it or are fearing it, but also for payers, if they have to cover for the next treatments to come in if patients are progressing.

And actually, we observed a 70% reduction in the risk of the need for next anticancer treatments, the medians were 19 months only in the control arm versus 66 months in the early enzalutamide arm. So obviously a big, big difference. And I think all those things make for a little bit of a scenario of earlier use of AR inhibitors, the new standard of care for these patients with nonmetastatic CRPC in a rapidly rising PSA.

Alicia Morgans: I completely agree. And just to piggyback on your comments about prolonging time to next therapy, because in many cases that next therapy is going to be a chemotherapy because we know that sequencing these error directed therapies one after the other is generally fairly ineffective, particularly in a time of COVID-19 when we are trying to reduce myelosuppression in patients to keep them safe in the setting of a possible infection. I think that's a really important endpoint and very important to know about enzalutamide.

Karim Fizazi: I agree. I agree.

Alicia Morgans: So as we wrap up, do you have any closing thoughts on the PROSPER trial and this exciting overall survival data from the New England Journal as well as virtual ASCO?

Karim Fizazi: Well, I guess it's impressive to see a Phase III trial after phase three trial with positive overall survival data reported with enzalutamide, and generally speaking, this is also true with AR access inhibitors, including, enzalutamide, abiraterone, darolutamide, apalutamide... These drugs work. And it really seemed that earlier is better. So I think this is a very important lesson to learn. And I'm also thrilled to see even earlier use of these agents in situations where patients are potentially in a curative situation.

Alicia Morgans: Absolutely. And I look forward to hearing more data come out with potentially even earlier use of these agents because they certainly seem to work well in the settings in which we've tested them. And I appreciate your continued efforts, and certainly your time today, sharing all these considerations about enzalutamide in the nonmetastatic CRPC setting. Thank you so much for your time.

Karim Fizazi: Thank you very much, Alicia.