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GnRH Antagonists Versus GnRH Agonists

Insights From: Susan F. Slovin, MD, PhD, Memorial Sloan Kettering Cancer Center; Dipti Gupta, MD, MPH, Memorial Sloan Kettering Cancer Center
Published: Wednesday, Apr 10, 2019



Transcript: 

Susan F. Slovin, MD, PhD: While GnRH [gonadotropin-releasing hormone] agonists have been the mainstay of treatment, the development of GnRH antagonists have really changed, we think, the cardiovascular milieu. Peter Albertsen [MD] in a very well received article a number of years ago, actually looked at patients who were treated with a GnRH antagonist and actually found that the absolute risk of cardiovascular events was markedly reduced compared with those patients who had received a GnRH agonist. And now that opens the question of really how do we circumvent this problem with cardiovascular risks? And what we’re again talking about is the risk of stroke, a patient who needs to go for coronary angioplasty, patients who may need to undergo a bypass. All are major issues for patients, and will patients develop worsening diabetes? Some people do. Will they have greater problems with hypertension? Some people do, but it’s not across the board. So how do we best address it?

The data are very tantalizing. It’s tantalizing in the sense that if we have a means of really controlling the risk that a patient will have a major cardiovascular event, a heart attack, a stroke, etcetera, then we need to implement that medication. And so to address that, there is a 900-patient randomized phase III study that is largely taking place in Europe and in some centers in the United States called the PRONOUNCE Trial.

As noted, it’s randomized and it is looking at patients who have pre-existing cardiovascular disease as ascertained by a panel of, of tests that involve a major cardiac workup. Patients are randomized to receive either monthly Lupron, or leuprolide, for approximately 6 months, versus monthly degarelix, or a GnRH antagonist otherwise known as Firmagon. The goal here is to determine are you finding a difference in these major cardiovascular events. Now what needs to be underscored here is this is not a urology trial. This is the first prospective, not retrospective, not a meta-analysis, not a registry trial—the first prospective trial that actually will look at the major cardiovascular events that can occur if you’re on a GnRH antagonist or agonist. The duration of the study is roughly 6 months with the option to maintain the patient on for an additional 12 months, or per MD discretion.

While this is not a urology trial, of course it is a cardiology trial, and I am working with Dr Matthew Roe [MD, MHS], and Dr Chiara Melloni [MD] at Duke University, who are the coinvestigators on this trial, and they are the cardiologists who really oversee all aspects of the trial.

What’s also very important and is first in 2 other objectives, is that in addition to being a cardiovascular trial, it’s the first trial to prospectively look at inflammatory cytokines and other markers, potentially biomarkers, of cardiovascular risk, and that could include subsets of troponins as well. And also I think more importantly from the oncologist’s standpoint, is this is the first one that will look at the effects, prospectively, of either an antagonist or an agonist on the immune system and immune populations.

You know many of us have always wondered when we’re developing clinical trials with regard to immunotherapies, we’re dealing with much more advanced patients. In fact, most of our patients are older. They have pre-existing comorbidities, and it’s our goal not only to treat them with hormones but for clinical trials should their disease become resistant to current therapies.

Interestingly in going forward, the development of clinical trials can be hampered by not really understanding the immune system. We know that Lupron does suppress certain cell populations. We don’t know, however, exactly what the time course is. We don’t know really how an antagonist works on the internal immune milieu within the prostate, or in the bone marrow itself, or peripheral blood. So these 3 goals would be really amazing in terms of how we can finally get answers to these questions.

So right now, the phase III PRONOUNCE trial is accruing very briskly, and we hope in the next several years at least to have an answer to how do we help people with cardiovascular disease, and is a GnRH antagonist or agonist equal to, noninferior, or is one really better than the other. So this is exciting for all of us.

Transcript Edited for Clarity
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Transcript: 

Susan F. Slovin, MD, PhD: While GnRH [gonadotropin-releasing hormone] agonists have been the mainstay of treatment, the development of GnRH antagonists have really changed, we think, the cardiovascular milieu. Peter Albertsen [MD] in a very well received article a number of years ago, actually looked at patients who were treated with a GnRH antagonist and actually found that the absolute risk of cardiovascular events was markedly reduced compared with those patients who had received a GnRH agonist. And now that opens the question of really how do we circumvent this problem with cardiovascular risks? And what we’re again talking about is the risk of stroke, a patient who needs to go for coronary angioplasty, patients who may need to undergo a bypass. All are major issues for patients, and will patients develop worsening diabetes? Some people do. Will they have greater problems with hypertension? Some people do, but it’s not across the board. So how do we best address it?

The data are very tantalizing. It’s tantalizing in the sense that if we have a means of really controlling the risk that a patient will have a major cardiovascular event, a heart attack, a stroke, etcetera, then we need to implement that medication. And so to address that, there is a 900-patient randomized phase III study that is largely taking place in Europe and in some centers in the United States called the PRONOUNCE Trial.

As noted, it’s randomized and it is looking at patients who have pre-existing cardiovascular disease as ascertained by a panel of, of tests that involve a major cardiac workup. Patients are randomized to receive either monthly Lupron, or leuprolide, for approximately 6 months, versus monthly degarelix, or a GnRH antagonist otherwise known as Firmagon. The goal here is to determine are you finding a difference in these major cardiovascular events. Now what needs to be underscored here is this is not a urology trial. This is the first prospective, not retrospective, not a meta-analysis, not a registry trial—the first prospective trial that actually will look at the major cardiovascular events that can occur if you’re on a GnRH antagonist or agonist. The duration of the study is roughly 6 months with the option to maintain the patient on for an additional 12 months, or per MD discretion.

While this is not a urology trial, of course it is a cardiology trial, and I am working with Dr Matthew Roe [MD, MHS], and Dr Chiara Melloni [MD] at Duke University, who are the coinvestigators on this trial, and they are the cardiologists who really oversee all aspects of the trial.

What’s also very important and is first in 2 other objectives, is that in addition to being a cardiovascular trial, it’s the first trial to prospectively look at inflammatory cytokines and other markers, potentially biomarkers, of cardiovascular risk, and that could include subsets of troponins as well. And also I think more importantly from the oncologist’s standpoint, is this is the first one that will look at the effects, prospectively, of either an antagonist or an agonist on the immune system and immune populations.

You know many of us have always wondered when we’re developing clinical trials with regard to immunotherapies, we’re dealing with much more advanced patients. In fact, most of our patients are older. They have pre-existing comorbidities, and it’s our goal not only to treat them with hormones but for clinical trials should their disease become resistant to current therapies.

Interestingly in going forward, the development of clinical trials can be hampered by not really understanding the immune system. We know that Lupron does suppress certain cell populations. We don’t know, however, exactly what the time course is. We don’t know really how an antagonist works on the internal immune milieu within the prostate, or in the bone marrow itself, or peripheral blood. So these 3 goals would be really amazing in terms of how we can finally get answers to these questions.

So right now, the phase III PRONOUNCE trial is accruing very briskly, and we hope in the next several years at least to have an answer to how do we help people with cardiovascular disease, and is a GnRH antagonist or agonist equal to, noninferior, or is one really better than the other. So this is exciting for all of us.

Transcript Edited for Clarity
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