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.
OncLive: Can you first describe the difference between an agonist and an antagonist?
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.
Please provide some background on the PRONOUNCE study.
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?