Alicia Morgans: Hi, I'm so excited to have here with me today Dr. Susan Slovin, a friend and attending physician and member at Memorial Sloan Kettering where she is a GU Medical Oncologist. Thank you so much for being here today, Susan.

Susan Slovin: Thank you, Alicia. Pleasure to be here.

Alicia Morgans: Wonderful. So you have done so much work with the PRONOUNCE trial and I'd love to hear an overview again of what that trial is and then give us a little insight on where things are going.

Susan Slovin: Thanks, Alicia. It's my pleasure to be here and give you a bit of an update on the PRONOUNCE trial. Actually, since the last time we spoke about it, a lot of good things are happening. You may remember the PRONOUNCE trial is really the first Phase III prospective trial comparing a GnRH antagonist with a GnRH agonist with the endpoints of major adverse cardiovascular events, or MACES. It gives us the opportunity to really explore how cardiovascular disease is not only affecting our patient's wellbeing on androgen deprivation therapy, but it's going to give us for the first time a lot of different endpoints among which will be the endpoint of myocardial infarction, death or even strokes.

In addition, we will be looking at inflammatory cytokines. It'll be for the first time the opportunity to determine whether or not androgen deprivation therapy affects immunologic biomarkers. And overall, I think is going to give us some conclusion as to how we best use androgen deprivation therapy. At the last time we spoke, we were really gearing up. So I'm very pleased to say that to date we have over 400 patients that have been successfully enrolled-

Alicia Morgans: Wow.

Susan Slovin: At no less than 100 different centers-

Alicia Morgans: Wow.

Susan Slovin: Both in Europe and in the United States. The triple endpoints I've already mentioned to you with myocardial infarction, stroke or death is being major MACES, so to speak. To date, I would say that every patient who comes in has been very well adjudicated. I think a lot of things that need to be remembered is that number one, this is not a urologic trial, contrary to popular belief. Number two, this is really a cardiovascular trial because for the really first time we're learning about the effects of androgen deprivation on the cardiovascular system. More importantly, people just assume it's just a general enrollment, but the adjudication process is extremely thorough.

My co-investigators, which are our cardiologist, Dr. Matthew Roe and Dr. Chiara Melloni at Duke are really extremely involved in the enrollment and adjudication process. And by adjudication, what we're talking about is really looking at the enrollment criteria. There are certain parameters, the ankle-brachial indices, among other historic events that the patient may or may not have had that will mandate eligibility. It's quite an awesome task time-wise in terms of really getting a sense of how to make sure that whatever the cardiovascular event is really due to drugs and not to any other competing or antecedent problem. So that's really where we are. So we are a little bit more than a third of the way through. Hopefully, we will be still on schedule to make the end of 900 patients at some point within the next probably two years.

Alicia Morgans: Wow. That is a huge endeavor, but it's important I think to get that number of patients. Because like you said, this is not a urologic outcome-focused trial. This trial is really focused on understanding the cardiovascular risk that may be associated with these drugs. And I love that there's a central adjudication because cardiovascular events and risk going into those events actually is a really complicated thing. And really just to emphasize, if you want to comment, that your co-investigator is a cardiologist and so that expertise is actually critical to this.

Susan Slovin: Absolutely. Both Matt and Chiara are based at Duke, so Duke has an outstanding cardiothoracic and cardiovascular service there. I think the most important thing that one has to keep in mind is there are differences in practices in Europe versus the American cardiologists, so there's a lot of different things that have to be taken into account when actually doing the trial and analyzing the data. But the scrutiny, I think, is incredible in terms of the amount of work really just in going on a patient by patient enrollment. It's extraordinary.

I think the most important thing is that this is a prospective trial. We really have no data. If you go back here to the 1970s, there are very small reports, or they're all retrospective, or case-control studies that are just looking at the effects of hormonal therapy overall in general wellbeing, whether preclinical studies in mice. But this is the first time we have the opportunity to really look for changes in inflammatory cytokines, cellular populations, not to mention a variety of different proponents that are associated with cardiovascular events.

It's interesting though, more recently, I think you're probably aware of this as well. There was a retrospective report about abiraterone causing some increased cardiovascular risk. So the old days of saying that somebody has diabetes, hypertension, it's just not enough. There's a lot more that's going on with these patients than we really gave credibility two years ago.

Alicia Morgans: I agree. And I think it is so fascinating that you're trying to really unravel the biology behind these events. Because as you said, we don't completely understand it and what we can see is there appear to be associations in some of these trials that are not prospective randomized trials. But this study with a primary cardiovascular endpoint is really able, I think, to really kind of unearth the pieces there and dig into the biology. So can you tell us, before we wrap up, just a touch more about the correlatives that are going to help us understand, you said the inflammatory cytokines and others, how that will help us understand better?

Susan Slovin: Well, a lot of the blood samples will be banked, at least for the kind of retrospective work that I'm interested in, which is the immunologic aspects of it. But there are a variety of inflammatory cytokines. I think they're too numerous to even be mentioned at this point. Whereby, we are looking for changes at different time points in terms of what's really happening in the cardiovascular symptoms.

The interesting thing is that there are a lot of preclinical studies that are done about the generation of atherosclerotic plaques. I think we all know that, but there are preclinical models that actually are looking at the effects of androgen deprivation therapy in these models. So whether or not that will actually correlate to what we are seeing in patients really remains to be determined. So it's extremely exciting. We are also working with several very nationally and internationally known cardiologists who are giving their insight into the trial. So this is ... I'm becoming a cardiologist in my dotage.

Alicia Morgans: Wonderful. I mean, you could really anticipate a day when we might start patients on a drug, look for a particular inflammatory signature that might suggest that they're at higher risk for cardiovascular events, and then alter our decisions around that. Of course, requiring additional prospective trials to do something like that. But this is just further personalizing our approach to medicine and prostate cancer, which is fascinating.

Susan Slovin: Yes, you're absolutely right, Alicia. I think the most important thing that's going to come with this is this is likely to change the standard of care. Now, I have no biases. There are differences in a degarelix, a GnRH antagonist in the sense that it will drop the certain testosterone level faster within 24 to 48 hours. You don't have the LH, FSH flares that occur very often compared with the GnRH analog. But I think that if it turns out that we are going to find out that one is better than the other in terms of reducing cardiovascular risk, it's very likely to change how we're going to use these drugs and how we practice. So there's a lot to be determined as a result of this trial.

Alicia Morgans: Absolutely. Well, I sincerely thank you for sharing your insights, for doing this work in the first place, and helping us get these answers for our patients, for ourselves as clinicians. Thank you for your time.

Susan Slovin: Thanks so much for having me.