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Susan F. Slovin, MD, PhD, discusses the multinational PRONOUNCE study and how the results may affect the treatment of patients with prostate cancer.
Susan F. Slovin, MD, PhD
Preliminary data suggest that patients with cardiovascular disease being treated for metastatic prostate cancer may experience fewer cardiovascular events when treated with a GnRH antagonist, such as degarelix (Firmagon), compared with a GnRH agonist.
The currently accruing PRONOUNCE study is comparing the occurrence of major adverse cardiovascular events in patients with prostate cancer and cardiovascular disease receiving degarelix or the GnRH agonist leuprolide (NCT02663908). This is a multicenter, randomized, controlled trial of 900 patients with prostate cancer and concomitant cardiovascular disease.
Investigators will be assessing for major adverse cardiovascular events, such as myocardial infarction, stroke, or death. These patients will be randomized 1:1 to receive either degarelix or leuprolide according to label recommendations for a maximum of 1 year.
In an interview with OncLive, Susan F. Slovin, MD, PhD, the co-principal investigator of PRONOUNCE and a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed this multinational study and how the results may affect the treatment of patients with prostate cancer.Slovin: A GnRH agonist, such as leuprolide, essentially tells the brain not to send a signal to the gonads to make testosterone. Because there is a feedback loop between the brain and the gonads, the gonads immediately start to make more testosterone to try to get the attention on the brain and say, "Here I am. Tell me what to do." Over a period of time, that connection just does not happen. The testes shut down, and it also has to do with follicle-stimulating and luteinizing hormones, but the point is that, at the end of the day, the testes do not receive that signal. They shut down, and the man goes through the equivalent of a chemically induced menopause.
The benefit of a GnRH agonist is that you don't have that sudden surge of testosterone. Why we are concerned about that sudden surge of testosterone is because if someone has preexisting metastatic disease in the bone, or a huge prostate that is causing obstructive symptoms, that sudden outpouring of testosterone can cause the cancer to worsen. People could have pain in the bone, worsening of obstruction, and very often we have to give a second pill—an antiandrogen—in order to prevent that testosterone from binding to the tumor cell and make it grow. This means we have to pretreat patients.
GnRH antagonists, such as degarelix, work very differently, as they bypass that time where that surge occurs. There is no surge [in testosterone] and castration can take place within the next 24 to 48 hours. With a GnRH agonist, it takes considerably longer. If patients come in and you want to treat them rapidly, you would use an antagonist. It seems to work much faster in getting that testosterone level down and it’s well tolerated. Again, it is user’s choice—we are not saying that one is better than the other in terms of getting the job done regarding castration. The mechanism of action is a little bit different, but they both get the job done in terms of castration. Cardiovascular disease is still a leading cause of death in men and women. Several years ago, it came under evaluation by a variety of physicians—including radiation oncologists and urologists—that there may be some increased risk of cardiovascular events, such as myocardial infarction and strokes, in patients who are receiving a GnRH agonist, such as leuprolide, which is currently being used for the treatment of metastatic prostate cancer.
This was taken very seriously in both in the United States and Europe, such that black box warnings were listed on the products to indicate that there may be a disadvantage in giving patients these drugs because it could increase cardiovascular events. This is not considering that men who have metastatic prostate cancer are often older, have preexisting cardiovascular problems, hypertension, and diabetes, in addition to having had some sort of previous cardiovascular event—these are people who are at high risk.
Therefore, we asked, “Is there any background to this—is this a real event or not?” This was largely based on observational and retrospective studies that were done by radiation oncologists and a variety of other physicians to indicate that there was a very high risk. Given now that we have new drugs, particularly a GnRH antagonist degarelix, preliminary data have suggested that the amount of cardiovascular side effects in men receiving a GnRH antagonist might be fewer than men who receive a GnRH agonist. Very simply put, is it better to take a drug that does not allow a flare in testosterone levels to occur?
This has nothing to do with marketing; it has everything to do with improving the care of men with known cardiovascular disease. Do we want to improve and make it safer for them? Or, is there something that we are doing that is exacerbating preexisting conditions? The trial is currently ongoing. It is a prospective 900-patient trial, in which men are randomized to either a GnRH agonist or antagonist over the course of 1 year. It is open to patients who are newly diagnosed with metastatic disease. It is also open to patients who might be undergoing definitive radiation therapy and may need upfront neoadjuvant hormonal ablation. This is going to take a while to accrue—it is multinational, and there is a vigorous effort to complete this trial within the next 2 to 3 years.
This phase III trial of 900 men is really the first of 3 aspects. The first thing to do is a prospective comparison of a GnRH agonist versus antagonist. We must first look at biomarkers associated with cardiovascular events, including specific B-type natriuretic peptide and cytokines. This is the first study to look prospectively at what happens to the immune milieu and the immune cells under the influence of the GnRH agonist or antagonist. I can tell you that we know very little—the first few papers looking at the effects on the immune system using a GnRH agonist were probably in the 1970s. However, no one has ever looked forward—we've never had a clean slate in which we can evaluate it.
These 3 objectives are the first of their kind attempting to understand what is going on. This may also be important in terms of designing future trials from the immune system vantage point and other aspects. In fact, there are preclinical models with cardiovascular issues, such as atherosclerotic plaque formations, that under the influence of the GnRH agonist, is very different in terms of worsening compared with an animal that is given an antagonist. There are preclinical data showing that there may be something very different about the plaque stability in a patient who might be going on to receive an antagonist versus an agonist. This is very exciting for all of us; it is not going to be completed very fast, but at least it will answer an unanswered question of the last 30 years.Either the GnRH agonist or antagonist is reasonable. Most of these people will come in already on medications to reduce the risk of having an event, so the question is, “Can those risks be worsened in any way?” For somebody who has an extremely high risk of metabolic syndrome, which is hypercholesterolemia and hypertension, weight gain, and obesity, it is often prudent to speak with their primary doctor regarding concerns about cardiovascular risk. We actually have very strict criteria in terms of what we are looking at in the trial. We are looking at somebody in the trial who is on medication for their cardiovascular risk and who has had a myocardial infarction or a stroke. The idea is, are we preventing anything new from happening?
This is a very fair question being asked. Are we making anyone higher risk? The answer is probably not in terms of a major event. If someone is terribly ill and has [New York Heart Association] class 3 or 4—meaning that they are really a cardiac cripple—I would have a very long discussion with them, their primary doctor, and their cardiologist about the relevance of it. It is very rare that we see these patients though.If this is a positive study, it will likely result in a change in clinical practice. It is more than possible that people will be using a GnRH antagonist more routinely. There are concerns with the GnRH causing some local skin reactions that may not be tolerated by some patients, but the point is that it would change practice by not needing to use an antiandrogen before giving an injection of a GnRH agonist. It’s one less pill to take, one less medicine to worry about, and you are guaranteed to get to castrate levels within 24 to 48 hours—which is much faster than a GnRH agonist. We are very eager to see how this pans out.
It is a very reasonable study, and the cardiac criteria are very stringently reviewed by Dr Matthew T. Roe, who is the co-principal investigator on the trial with me, and Dr Chiara Melloni, both of whom are from Duke University School of Medicine. They are extremely enthusiastic in terms of making sure that everyone who goes on the trial is an appropriate candidate. Each patient is reviewed very thoroughly before going into formal screening for the trial.
The most important takeaway message is that this is not a urology trial. This is a cardiovascular trial in patients who have prostate cancer. But, who sees the patients with prostate cancer? Radiation oncologists, urologists, and medical oncologists.
Slovin SF, Melloni C, Mansor-Lefebvre S, Neijber A, Roe A. A multicenter, randomized, controlled trial comparing the occurrence of major adverse cardiovascular events (MACEs) in patients (pts) with prostate cancer (pc) and cardiovascular disease (CVD) receiving degarelix (GnRH receptor antagonist) or leuprolide (GnRH receptor agonist). J Clin Oncol. 2018;36 (suppl 6S; abstr TPS395).