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Significance of GnRH Antagonists in Prostate Cancer

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: 

Susan Slovin, MD, PhD:
What’s interesting is that if you look at the GnRH antagonists, of which degarelix is probably the only one out there at the moment, there is a very distinct mechanism of action. LHRH agonists cause a surge of FSH, LH, and testosterone which, again, can be blocked by using antiandrogens. The difference is that suppression of FSH is really not maintained for a long period of time. Then, you get these microsurges of LH and testosterone on repeat injections. It’s given people pause about, is that a reason why we’re seeing androgen resistance? Is that the reason why some people reach a castrate level of testosterone of 50, whereas others may go down as low as 10? Is that maybe a reason why people are not covered as well as they should be?

If you look at the antagonists, you immediately get a suppression of FSH, LH, and testosterone—within a very short period of time. But it’s prolonged, and you don’t have those microsurges that may be responsible for the irregularities that you sometimes see with people’s PSA levels.

Another reason why degarelix is of interest is because there had been a pooled analysis that looked at a variety of treated patients and cardiovascular history. And here, too, we have 6 phase III/IIIb trials comparing degarelix with LHRH agonists. As you can see, about 2500 patients were randomized. About 1500 received degarelix, of which about 31% had some cardiovascular history. On the other arm, close to 850 went on to a LHRH agonist. Close to 450 went on Zoladex, or goserelin. The other roughly equal number went on Lupron. Of that group, about 29% had some form of cardiovascular history.

The history, as Dr. Gupta will talk about, looked at myocardial infarction, some sort of coronary artery event, stroke, angina, a bypass, or even revascularization. If you look on the Y axis, this is the cardiovascular event leading to death. The light blue area on your left represents the LHRH agonist, showing that about 14.7% of those patients had a cardiovascular event. Whereas on the right side, or deep blue area, in those patients who were on a GnRH antagonist, it was 6.5%. That was a 56% relative risk reduction with a P value of 0.002—clearly significantly fewer cardiovascular events during the first year of treatment. Again, 4.5 versus 8.4 with an absolute risk reduction of 8.2. The conclusion had been that you had an absolute risk reduction, which was 8.2, with a need to treat to avoid at least 1 cardiovascular event or death. And here, the cardiovascular events were exceptionally well annotated. They were in arterial embolic/thrombotic events, hemorrhagic/ischemic strokes, and the like.

Transcript Edited for Clarity 


 
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Transcript: 

Susan Slovin, MD, PhD:
What’s interesting is that if you look at the GnRH antagonists, of which degarelix is probably the only one out there at the moment, there is a very distinct mechanism of action. LHRH agonists cause a surge of FSH, LH, and testosterone which, again, can be blocked by using antiandrogens. The difference is that suppression of FSH is really not maintained for a long period of time. Then, you get these microsurges of LH and testosterone on repeat injections. It’s given people pause about, is that a reason why we’re seeing androgen resistance? Is that the reason why some people reach a castrate level of testosterone of 50, whereas others may go down as low as 10? Is that maybe a reason why people are not covered as well as they should be?

If you look at the antagonists, you immediately get a suppression of FSH, LH, and testosterone—within a very short period of time. But it’s prolonged, and you don’t have those microsurges that may be responsible for the irregularities that you sometimes see with people’s PSA levels.

Another reason why degarelix is of interest is because there had been a pooled analysis that looked at a variety of treated patients and cardiovascular history. And here, too, we have 6 phase III/IIIb trials comparing degarelix with LHRH agonists. As you can see, about 2500 patients were randomized. About 1500 received degarelix, of which about 31% had some cardiovascular history. On the other arm, close to 850 went on to a LHRH agonist. Close to 450 went on Zoladex, or goserelin. The other roughly equal number went on Lupron. Of that group, about 29% had some form of cardiovascular history.

The history, as Dr. Gupta will talk about, looked at myocardial infarction, some sort of coronary artery event, stroke, angina, a bypass, or even revascularization. If you look on the Y axis, this is the cardiovascular event leading to death. The light blue area on your left represents the LHRH agonist, showing that about 14.7% of those patients had a cardiovascular event. Whereas on the right side, or deep blue area, in those patients who were on a GnRH antagonist, it was 6.5%. That was a 56% relative risk reduction with a P value of 0.002—clearly significantly fewer cardiovascular events during the first year of treatment. Again, 4.5 versus 8.4 with an absolute risk reduction of 8.2. The conclusion had been that you had an absolute risk reduction, which was 8.2, with a need to treat to avoid at least 1 cardiovascular event or death. And here, the cardiovascular events were exceptionally well annotated. They were in arterial embolic/thrombotic events, hemorrhagic/ischemic strokes, and the like.

Transcript Edited for Clarity 


 
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