Agonists and Antagonists: A Review of What is Known and Recent Data on Disease-Related Outcomes from a Pooled Analysis

Agonists and Antagonists: A Review of What is Known and Recent Data on Disease-Related Outcomes from a Pooled Analysis

I’ve been asked to talk about androgen deprivation therapy and what we know about it and what we don’t know about it. We’ve been dealing with this since 2002, the 2000s when abarelix came along as an alternative to an LHRH agonist and then we got to 2008 when we had degarelix and basically you can see the differences that are listed here. I don’t need to go over them but just to say they are dramatically different compounds and they have different affects in terms, particularly of surge of testosterone, of microsurges of FSH suppression the two products differ fundamentally. As a result of these differences I think combined androgen blockade has been around for many years and we’ve argued it left and right, we’ve had numerous meta-analyses but combined androgen blockade in summary does not abrogate the initial testosterone surge which is intrinsic with LHRH agonists.

Marketed anti-androgens do somewhat inhibit but do not completely inhibit the cytoplasmic androgen receptor and there is a possibility that when you expose it in that manner you may be inducing a resistant phenotype by partial blockade. Again, needs to be proven but one of the first maneuvers that happens when the testosterone rises and someone’s on CAB is you with draw the anti-androgen and you do see a 25% drop on average overall in PSAs which is short-lived because the androgen receptor does change and come back again.

Again, we don’t know if FSH is involved in the development of prostate cancer. There’s a lot of basic science data which would indicate that it is but it has to be proven and these are the future directions that we’ll take.

The antagonists were developed to completely avoid the testosterone surge to cause a more rapid reduction in testosterone. It doesn’t affect the androgen receptor; it’s devoid of the anti-androgen adverse events and it does cause we now know more profound suppression of FSH.

A couple of questions that have become answered in recent years; what is an appropriate testosterone level. Its 20 nanograms per deciliter. It shouldn’t be 50 and I think in future directions going forward we, as urologists, should insist that that gets changed, that we have an effective reduction in testosterone not something mandated by the FDA as being okay.

The other questions that we ask are do differences exist between the efficacy and benefits of GnRH agonists and antagonists particularly in terms of time to castration and castration onset and PSA suppression. Also PSA progression, is that different? Are there significant differences in the safety profile? These are all things that are currently being looked at.

In terms of testosterone the question is answered in my opinion. We had the Morote data, we had the Perachino data which were teasers, there wasn’t enough to draw any conclusion; they were hypothesis generating and then we had the data from the Canadian data which really proved the point in over 600 patients and those patients who had a testosterone level you see it at the bottom there that’s 50 or more compared to those who had a low testosterone of 20 or less on the top there was a profound difference in the rate of progression of their disease so I think 20 is the accepted number.

Then we look at what’s the difference between an agonist and antagonist. It takes one amino acid change to make an agonist it takes seven to make an antagonist.

There has been a head-to-head comparison. It was a non-inferiority trial, it was a CS21, and you all know the data. As I mentioned it also had a number of secondary objectives. When you look at the primary endpoint it succeeded. It was non-inferior so the antagonist was non-inferior to the agonist in terms of testosterone suppression below 50. Big deal. The secondary endpoints however were really interesting. The proportion of patients with testosterone surge between the two agents significantly different. The proportion of patients with testosterone less than 50 at Day 3 significantly different. The percentage change in PSA from baseline to Day 28 and time to PSA failure significantly different. Frequency of PSA progression, significantly different and no difference except for injection site reactions in terms of toxicity.

When you look at reducing the risk of death, and this was an unexpected finding, we found that there was a substantial difference in terms of PSA progression, or castrate resistance or death. It was found that it was more prominent that you saw that in the patients with the higher PSA or the higher volume of disease. Also Vin Schroder showed that serum – – phosphatase control was considerably different. If you’re on the antagonist it stays down over the year of this study. If you were on the agonist it gradually comes back up to normal as you get to the last four or five months.

Then the FDA mandated an extension study. In the extension study they said we want you to stop the patients on the agonist and convert them across to the antagonist because we want to make sure in view of previous data that there’s not a more profound escape phenomena which was seen in earlier versions of the antagonist.

What happened? Basically when they converted patients over from the LHRH agonist to the antagonist we saw a surprising drop in FSH levels, 63% further drop. This was not new data. Marc Garnick could show them this in 2002 that the antagonist had a much more profound control of FSH.

I know I’m sitting here talking about FSH and you’re saying what the hell does FSH have to do with prostate cancer. This was a study that was produced by Radu. It was in the New England Journal and it showed that they stained for the FSH receptor, they also stained for the vascular endothelial cell markers, and they found that they were in the identical areas. They were at the leading edge of the tumor and there were more vessels of course in the tumor and where was the location of the majority of the vessels? At the periphery of the tumor which is exactly where you would expect them to be if this is an invasive tumor.

Getting back then to the crossover study when the patients were crossed over there was a difference in PSA progression between the two arms of the study and once you converted patients across from the agonist to the antagonist you saw the event rate drop back to what it was with the antagonists themselves. The failure curve shifted to benefit the patients.

The overall summary was that the antagonist offers faster castration onset and PSA suppression with no risk of clinical flare, longer PSA progression-free survival. The five year extension study the therapy was well tolerated and PSA progression was improved after crossover.

Then we need to look again and see what is the disease control in cardiovascular outcomes. We don’t have many randomized control trials but we have a number of Phase III trials which we can put together in the form of a pooled analysis and that was what was done here. There were three long-term studies and three short-term studies. All of them as you put them together had a large number of patients in the agonists and on the antagonists. I wanted to show patients were well balanced, there were 1,263 patients on the antagonist, and there were 657 patients on the agonist.

This is Larry Klotz’s data which was published in 2014, he was the lead author on the paper, and there was a superior overall survival for patients on the antagonist compared to the agonists. That doesn’t make sense. Very few patients died of prostate cancer of the year of this study so what did they die of? Cardiovascular complications. They also looked at the rate of musculoskeletal events which was significantly different and the rate of urinary tract infections.

Now we need to focus in perhaps on the cardiovascular events and see what’s going on. Is the risk of cardiovascular events increased with agonists versus antagonists?

You have to look at the ADT and the risk of cardiovascular event. ADT is associated with an increased risk of cardiovascular events when you use LHRH agonists it was linked to increased cardiovascular morbidity compared to orchiectomy. Men with a history of cardiovascular disease were the most at risk. The antagonist has a distinctly different mechanism of action so we may not see this difference if we’re using an antagonist.

This all started back in the late sixties when the estrogen data came out from the VA and you did see an improvement in survival from prostate cancer in patients treated with estrogens but this was muted by the rate of death for cardiovascular events by giving estrogen. There was no essential difference between the two.

Further studies, and this is a study which was published I think in 2011 showed that GnRH agonists also have an increased rate of cardiovascular events and CAB had a small amount, orchiectomy has a small amount too.

Then we have the D’Amico data which showed that men over 65 years of age receiving 6 months of ADT had shorter times to fatal myocardial infarction compared to radiotherapy alone.

Based on the studies what have been said so far if the increase in risk of cardiovascular disease in men treated with ADT that is orchiectomy, estrogens, or GnRH agonists appears to be 20 to 25% which is the same risk if you’re looking at a smoker versus a nonsmoker.

This was the pooled data. Over 2,000 patients, 1,401 on degarelix, the antagonist, 837 on the agonist. They were well balanced and as you looked at it this was patients with a history of a cardiovascular problem. There was a very significant difference in any cardiovascular event occurring when on the agonist versus that antagonist and the death rate was three times higher.

This is not a huge death rate but it may be a 4% difference. That’s four patients in every hundred. Also this is just a slide showing the same; it was a highly significant difference. When you looked at the common cardiovascular variables and you basically adjust them it still held true.

In summary when treated with degarelix compared to a GnRH agonist, patients with preexisting cardiovascular disease had significantly fewer events during the first year of treatment and had a relative risk reduction in death of 50% and an absolute risk of 8.2%? Why? We know it had metabolic changes. We might have GnRH receptor activation or we may have differences in FSH levels. The metabolic syndrome and the metabolic changes induced by ADT are different and the differences are highlighted here. I’m not going to go through them for the sake of time.

When you do look at plaques and all of us are at an age at this point when I look around that we may well have these plaques. I certainly want to have the plaque on the left rather than the plaque on the right because the plaque on the left is a stable plaque. You have a big cap, it’s rich in SMHC and matrix. You have poor lipid and you have little inflammatory cells present.

This is a GnRH receptors which are located in the smooth muscle cells in atherosclerotic plaques. Starting to see the message? This is how T lymphocytes are the key drivers of collagen metabolism in atherosclerotic plaques. You can see down on the bottom you have the T lymphocyte which release interferon gamma which interferes with collagen formation. You also then have CD40 which is released into the monocytic phagocyte there which then releases collagenases, et cetera, which breaks down the fibrotic cap. The result is a disruption of the fibrotic cap, plaque instability, and increased risk of thromboembolic complications.

Here it is in a cartoon form. There’s your GnRH receptor and the agonist on the T cell increased proliferation of activity, fibrotic cap disruption, the antagonist complete blockade, no increase in activity, no disruption of the cap.

I just want to show you these here. One of the reasons for explanation it’s difficult to attribute this to testosterone. It’s more than likely what I’ve just explained and there might be a punitive cause for FSH which is another future direction that we need to go in the next few years.

What does it mean for our patient? We should consider which therapy will treat the prostate cancer effectively, consider which will control the disease symptoms, and consider minimizing effects. If you don’t have cardiovascular disease history it probably doesn’t make a difference which one you’re on. If you have a history then you probably should be on the antagonist. If you have a high PSA you probably should be on the antagonist. If you have—again, this is tentative data it would appear as if you do better.

Finally, we’ve heard about future directions, where do we go. What do we do with abiraterone? Where do we put that? Where do we put ezsalutimide? We have AFFIRM, we have PREVAIL. Everything’s moving forward. I just had this up, I’m not going to show them but these are the key differences and it is a slide that’s available to you between the two studies. There were differences but both were dramatic in showing that the earlier you give it; you can give it pre-chemo, so you move forward. Now we have CHARTER. What’s going to be the future? Now we’re going to get chemo upfront. Probably a patient who presents with heavy volume metastatic disease is going to see LHRH therapy of some form be it an agonist or an antagonist and they’re going to see chemo and do we put abiraterone into that mix? Do we put enzalutamide into that mix? I would put it to you that the future is very exciting in how we manage this disease. There’s a load of work still to be done but the title of this is future directions so the future directions in the control of metastatic prostate cancer looks very bright but there’s a lot of work to do.

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