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Reducing the Risk for Cardiovascular Events: PRONOUNCE

Insights From: Dipti Gupta, MD, MPH, Memorial Sloan Kettering Cancer Center; Susan Slovin, MD, PhD, Memorial Sloan Kettering Cancer Center
Published: Wednesday, May 30, 2018



Transcript: 

Dipti Gupta, MD, MPH: There appears to be a difference in how we can achieve castrate levels of testosterone depending on what agent we choose, whether it’s a GnRH agonist or antagonist. But what seems obvious here is that we need a well-designed prospective study that looks at cardiovascular outcomes. I know you’ve been involved with something. Tell us more about that, Dr. Slovin.

Susan Slovin, MD, PhD: Dr. Gupta, you’re absolutely right. There are differences. What’s been very tantalizing is the fact that these studies have shown that cardiovascular risk is markedly diminished. The question is, what do we do about it? Because, again, everything was retrospective and we didn’t really have data.

There is a trial called the PRONOUNCE trial. This is a multi-center multinational randomized phase III trial. It is looking at major adverse cardiovascular events (MACEs). Again, those are defined as myocardial infarction (MI), sudden death, angina, or need for bypass in patients with prostate cancer who have preexisting cardiovascular disease. So, these patients are extremely well annotated. They will either present, for example, with metastatic disease or are patients who are going on to radiation, where they need good local control and hormonal therapy, or it’s felt, in the patient’s best interest, that hormonal therapy would be needed.

Dipti Gupta, MD, MPH: And these are high-risk patients?

Susan Slovin, MD, PhD: Absolutely. So, the patients will be randomized. Again, the recruitment process is somewhat comprehensive in the sense that every possible nuance of their cardiovascular history will be captured, including, but not limited to, cholesterol, triglycerides, and the like. Patients will first be randomized to a loading dose of degarelix, per the package insert, and then monthly degarelix for a year, and then leuprolide every 3 months. The expected accrual is 900 patients, with an interim analysis after 50% of anticipated cardiovascular events. The endpoint is really the time from randomization to the first adjudicated major adverse cardiovascular event. There will be a composite endpoint—death due to any cause, including nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. There will be a component that will look at any other symptoms that are related to prostate cancer—progression-free survival, failure rates, and the like.

I must underscore that this is not a urology trial. Yes, we’re using degarelix and we’re using Lupron (leuprolide). This is a cardiovascular trial, not a urology trial. This is the first prospective trial that is going to answer whether or not there is a substantial difference in terms of cardiovascular events, using a GnRH antagonist versus an agonist. The second point is that this is the first time that one would be looking at biomarkers, such as exploratory cytokines. And the third sense is, this would be the first to really look at the immune system and the impact of hormonal therapy on not only immune cytokines but also on the cellular populations. We all do vaccine trials. We use Lupron rather indiscriminately in those trials, and we’re really not sure how it modulates everything.

Dipti Gupta, MD, MPH: So, it will fill a major gap in the literature?

Susan Slovin, MD, PhD: Absolutely.

Transcript Edited for Clarity
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Transcript: 

Dipti Gupta, MD, MPH: There appears to be a difference in how we can achieve castrate levels of testosterone depending on what agent we choose, whether it’s a GnRH agonist or antagonist. But what seems obvious here is that we need a well-designed prospective study that looks at cardiovascular outcomes. I know you’ve been involved with something. Tell us more about that, Dr. Slovin.

Susan Slovin, MD, PhD: Dr. Gupta, you’re absolutely right. There are differences. What’s been very tantalizing is the fact that these studies have shown that cardiovascular risk is markedly diminished. The question is, what do we do about it? Because, again, everything was retrospective and we didn’t really have data.

There is a trial called the PRONOUNCE trial. This is a multi-center multinational randomized phase III trial. It is looking at major adverse cardiovascular events (MACEs). Again, those are defined as myocardial infarction (MI), sudden death, angina, or need for bypass in patients with prostate cancer who have preexisting cardiovascular disease. So, these patients are extremely well annotated. They will either present, for example, with metastatic disease or are patients who are going on to radiation, where they need good local control and hormonal therapy, or it’s felt, in the patient’s best interest, that hormonal therapy would be needed.

Dipti Gupta, MD, MPH: And these are high-risk patients?

Susan Slovin, MD, PhD: Absolutely. So, the patients will be randomized. Again, the recruitment process is somewhat comprehensive in the sense that every possible nuance of their cardiovascular history will be captured, including, but not limited to, cholesterol, triglycerides, and the like. Patients will first be randomized to a loading dose of degarelix, per the package insert, and then monthly degarelix for a year, and then leuprolide every 3 months. The expected accrual is 900 patients, with an interim analysis after 50% of anticipated cardiovascular events. The endpoint is really the time from randomization to the first adjudicated major adverse cardiovascular event. There will be a composite endpoint—death due to any cause, including nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. There will be a component that will look at any other symptoms that are related to prostate cancer—progression-free survival, failure rates, and the like.

I must underscore that this is not a urology trial. Yes, we’re using degarelix and we’re using Lupron (leuprolide). This is a cardiovascular trial, not a urology trial. This is the first prospective trial that is going to answer whether or not there is a substantial difference in terms of cardiovascular events, using a GnRH antagonist versus an agonist. The second point is that this is the first time that one would be looking at biomarkers, such as exploratory cytokines. And the third sense is, this would be the first to really look at the immune system and the impact of hormonal therapy on not only immune cytokines but also on the cellular populations. We all do vaccine trials. We use Lupron rather indiscriminately in those trials, and we’re really not sure how it modulates everything.

Dipti Gupta, MD, MPH: So, it will fill a major gap in the literature?

Susan Slovin, MD, PhD: Absolutely.

Transcript Edited for Clarity
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