Exploring the Nuances of the PRONOUNCE Trial - Celestia Higano

November 15, 2022

Alicia Morgans and Tia Higano discuss the PRONOUNCE trial, which evaluates the effects of degarelix and leuprolide on cardiovascular events in high-risk prostate cancer patients. Dr. Higano offers insightful explanations concerning the trial's methodology, highlighting its initial slow accrual and early cessation due to a futility analysis. However, she points out that the trial's results, which showed no significant difference in major cardiovascular events between the two treatments, may be more nuanced than they appear. She emphasizes the improvements in cardiovascular care over the past decade and wonders if the trial's stringent cardiac therapy requirements could have influenced the outcomes. Drs. Morgans and Higano also emphasize the importance of interdisciplinary cooperation, particularly with primary care physicians and cardiologists, when treating patients with prostate cancer to manage other health issues that may arise.


Celestia (Tia) Higano, MD, FACP, Adjunct Professor, Urologic Science, University of British Columbia, Medical Director, Prostate Cancer Supportive Care Program, Vancouver Prostate Centre, Vancouver, British Columbia

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. I'm so excited to be talking with Dr. Tia Higano. Thank you so much for speaking with me today.

Tia Higano: Hi, you're welcome, Alicia. It's nice to be here with you.

Alicia Morgans: Wonderful. Well, Tia, you have so many areas of expertise and passion and one of those areas is survivorship and cardiovascular health. And one thing that I'd really love to talk to you about is the recently published PRONOUNCE trial, which was evaluating a comparison of degarelix versus leuprolide and looking at a primary endpoint that was cardiovascular events in a high risk population, high risk for cardiovascular events, but they also of course had prostate cancer. So I'm wondering if you can talk us through this because I feel like there's a lot of misunderstanding of the study outcomes, maybe even the study itself. Maybe we can start there.

Tia Higano: Yes, I think you're right. First of all, PRONOUNCE was only presented to an international meeting in Europe at a cardiology meeting. And unfortunately, it hasn't really been given time at a large medical oncology or urology meeting. Either one would've been fine, given the population. But yes, as you said, the study was looking at men who were predicted to be at high risk for cardiovascular events based on the fact they already had a cardiovascular history. So that's one very important part of the study to understand. The study was basically powered off of the Albertson trial, which everybody knows now, was a study of six phase III studies that were pooled together and showed very clearly, of course, in that retrospective look that the antagonist, degarelix, relics did better than leuprolide, the agonist, specifically in this group of patients who had cardiovascular disease in terms of cardiovascular events.

So PRONOUNCE was originally supposed to have 900 patients and unfortunately, it did get off to a slow start in terms of accrual and that's another whole story. But once some of those issues were taken care of, the accrual was going fine. But understandably, the sponsor wanted to take a look at the cumulative events, the cumulative MACE events in the study. And when they did that, there were fewer than half of what was predicted with more than half of the patients accrued. So therefore, based on basically what was a futility analysis, they decided, "Listen, we just need to stop accrual because we could accrue 3000 patients and never really get to the end point." So I think that's one thing that people don't always understand. They just didn't stop it early because they wanted to, there was a good reason and the steering committee was involved in these decisions and so on.

So that's the first thing. And because those were cumulative events, it wasn't by arm. We were still hoping that we would see a positive outcome in the antagonist, but wasn't what we saw, as everybody knows. And I think it is true that the studies showed that there was no difference in major cardiovascular events based on the type of hormone therapy used. But there's some things I think that I don't think were mentioned in the publication. One is that the Albertson data had 2300, I think, patients total. And those patients were all treated between, I forget the exact date, but somewhere between 2005 and 2013. Now what's happened in between 2013 and when PRONOUNCE happened, there was at least a decade in there, and there's been major improvements in cardiovascular care during those years.

So first of all, if we had to do it all over again, we wouldn't have used that old data to power the study. The second thing is that if you look at what was predicted, what was predicted for the antagonist arm was 5% events. And what was predicted for the leuprolide arm was about 10%. And so the antagonist arm in PRONOUNCE had exactly 5%. So that was exactly where we expected it to be. Yet the leuprolide arm was half of what we expected it to be. So one of the questions is, because these patients in the trial were followed and had to be followed, that was part of the entry criteria. They had to be followed by cardiologists, they had to have their cardiac therapy optimized. Could that have made the difference and did that really shrink the potential effect in the agonist arm and offset that so that antagonist and agonist were the same? Because that's really what it looks like.

And it's the truth. If, ideally, you have every patient you're going to treat with ADT, possibly having optimal therapy, which honestly we know that's not the case. Maybe it doesn't matter. So I think those are important things for people to realize. It may not be evident in the publication.

Alicia Morgans: That is so important. Let's just highlight that again. So, we know that we didn't reach full accrual, but this was actually a very clear decision made based on futility, given the low event rate that was ultimately seen. But to your point, that event rate was actually what was expected in the degarelix arm, but in the leuprolide arm, this was half as much. Which really, I have thought, and I think it sounds like you agree, that the intensive management by the cardiologist addressing those reversible risk factors, works.

Tia Higano: Yes, exactly.

Alicia Morgans: That's great for patients who have access and for docs and patients who engage in that way.

Tia Higano: Right. And I think that's the next step that I think we need to go to, which is... I know that all of the side effects of ADT, bone marrow density, a DEXA scan, and now we're cardiac history. So there's two things with cardiac history that I think clinicians, whether they're urologists or medical oncologists or radiation oncologists, need to think about. And that's number one, did this person or has this person a prior cardiovascular history? But the second thing... So that's easy. Did you ever have a heart attack, stroke? But the second thing that has come out, and I think it's a no brainer once you really think about it, is the Cardio-Oncology Society has published guidelines recently and their suggestion, and it makes a lot of sense just because of normal cardiovascular risk, is that before prescribing ADT, we should do a quick cardiovascular assessment of what the risk of cardiovascular disease is in 10 years.

You do need to have some lab data and blood pressure, weight and so on in order to fill out this little thing. But it's on an app, it takes less than two minutes to put that information in if you have it, when you're sitting there with the app. And so if a person's risk is intermediate or high and intermediate starts at greater than or equal to, I think, 7.5% risk of a major cardiovascular event in 10 years, those patients are the ones who should be sent back to their PCP since they don't have a cardiac history. Maybe it's too early to send them to a cardiologist, but to make sure their therapy is optimized. Those patients often, even though they may not have hyperlipidemia, might be good candidates for a statin or if their glucose is a little off, hypertension not quite in control. So I think those could be relatively simple steps to optimize outcomes of our patients we're going to give ADT to. And not only that, it's just optimize their cardiac health anyway, since that's the number one non-cancer killer of men with prostate cancer and men.

Alicia Morgans: I completely agree. I think you're talking about the ASCVD risk calculator, which is really, I think, like you said, a wonderful app. You can have it on your phone or you can do it on the computer. It does require some information about patient age, I think races and their smoking status, lipids, blood pressure. But this is such a nice way to really help estimate for a patient. It of course raises the awareness that this is even something to consider. And for those patients at high risk, I think there is an indication, or at least I believe the cardiologist suggests that they are on a statin. Now that's not something that I would do and so to your point, engaging with primary care, engaging, if maybe the person has an arrhythmia, maybe there is something in their history, maybe they do have a cardiologist, but working with those team members to really optimize those risk factors is so important.

So I love that you raised that. And I do think that calculator, free easy, it's developed by the Cardiology Society. It's wonderful. So thank you. Thank you very much for bringing that up. Otherwise, I think that from my perspective as a medical oncologist, I make comments about blood pressure. I always make comments, "Get your lipids checked, make sure you're checking on your hemoglobin A1C". But it can be hard for an oncologist or urologist to do all that monitoring on his own or on her own. Do you engage routinely with these other doctors? Like you mentioned primary care. Is this something that you think we can do on a broad scale?

Tia Higano: Well, I think it is. Honestly, I did it myself just because that way I knew it would get done. And I think something to think about, is once it becomes formulaic in your clinic or if there's workflows and so on, I don't think it's really that hard to do. But ordinarily, I don't like to prescribe new anti-hypertensives and whatnot when the person has a primary care doctor and so I would make sure to somehow contact someone in the office. I don't have to talk to the doctor. I can even have my nurse talk to somebody in that physician's office and say, "Hey, we're starting this person on ADT. The oncologist thinks blah, blah, blah." And it can be an easy communication. It doesn't have to be complicated.

Alicia Morgans: I agree. And I certainly do the same in my practice. So if you had one recommendation or an of overall summary from PRONOUNCE, does this study definitively say that there's no difference between GnRH agonists and GnRH antagonists in terms of cardiovascular risk? Or is the message more nuanced?

Tia Higano: I think the message is more nuanced than that. And if you look at the European Cardio-Oncology guidelines, they still say there is a reason to think you might want to use an antagonist in a person with prior cardiovascular disease. The question you ask, "Well, is it definitive that they're the same?" And it's definitely more nuanced, but I do think there's still some things we just don't understand. And they do have different biologies. We know that. So I think we'll learn over time, I hope.

Alicia Morgans: More work to be done for you and for me. That's good and I think it's good for the patients. And I do think that, as you mentioned, engaging our cardiology colleagues, our primary care team members, to really address those reversible risk factors can reduce the risk most likely of some of these cardiovascular events. And because that's the major competing risk for our patients in terms of mortality, aside from their prostate cancer, we really do owe it to them.

Tia Higano: Absolutely. Now that we're making prostate cancer a chronic disease, we should deal with the other problems that can be fatal for men.

Alicia Morgans: Well, I'm glad that you're still working on it and I am glad to partner with you on all of those initiatives and I appreciate your time and your ongoing expertise.

Tia Higano: Oh, thank you. Nice to be here.