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Charles Ryan: I don't know if Paul Nguyen is here today, but I did want to point out that there are five questions regarding cardiovascular toxicity on this year's questionnaire, which is 2.7% of all questions. And it does highlight the importance of the issue. I think the previous talk was excellent in terms of helping educate us about what we should be looking for in our patients as they walk into our clinics.

The reality is our patients walk into our clinics with a load of risks for cardiac death. And I think of cardiac morbidity and toxicity as two things. One is it is a survivorship issue. You may treat a man with androgen deprivation therapy for six months or 18 months, and we just discussed that in the last session, and they may leave your practice and go live another five or 10 or 15 years, we hope, or longer. But they will carry with them the increased cardiac risk that comes from that experience that you induced in them when you use that androgen deprivation therapy. It is also an adverse event issue, which is to say you need to be monitoring for these events and these risks when you are treating the patient.

There are a number of data sets that we won't go through, all of them, that clearly demonstrate that androgen deprivation therapy is associated with increasing risks of heart failure, of myocardial infarction. Here is one, published about 15 years ago, which demonstrates that patients receiving localized radiation therapy, even with as short a duration of androgen deprivation therapy as four months, that those men who received androgen deprivation therapy versus those who did not experienced a worsening cardiovascular morbidity and mortality over time. So short-term duration can alter the future of our patients along this risk profile.

You should also know—we should also know—that our patients with localized disease are more likely to die of cardiovascular disease than prostate cancer within the first five to 10 years after we treat them, as is shown by the red bars here. But even as we keep patients alive longer with metastatic disease, we see that the rate of cardiovascular mortality is going up as the rate of prostate cancer mortality may be going down. So the more successful we get with treating prostate cancer, the more likely we may need to confront some of these other factors, in particular cardiovascular morbidity.

So think of it as two things. You've got early cardiac morbidity, you've got late cardiac morbidity, you've got primary cardiac morbidity caused by the drugs as you are administering them. And then you have all that other downstream stuff, like the diabetes that may occur, the obesity that may occur, the inactivity and the muscle loss that may occur. All that will contribute to this greater risk of cardiovascular morbidity.

So how great is the risk? I think it's safe to say, as we counsel patients, that androgen deprivation therapy may increase the risk of cardiovascular events by somewhere from 20% to 45%, as is highlighted by the hazard ratios looking at the various outcomes—CV death, myocardial infarction, stroke, et cetera.

One of the questions that we haven't really addressed as a field and should be addressing is why. Is it because testosterone has a cardioprotective effect? Is it because of the physiologic endocrine adaptations to a low-testosterone environment? Is it direct toxicity of the drugs on myocardial tissue or the vascular endothelium? I think we need more studies. There are some, and they're really interesting.

One, for example, a recent publication from China was very interesting looking at the role of FSH, follicle-stimulating hormone. FSH goes up when you give a GnRH agonist. It goes down or does not go elevated when you give a GnRH antagonist. And if you look at the—this is aortic root histo H&E stains from mice treated with leuprolide, degarelix, and then leuprolide plus bicalutamide. And you can see that there's an inflow of inflammatory cells that would contribute to plaque formation, as they also showed in this very, very nice paper.

That plaque formation is induced over time with the longer-term use. These drugs induce plaque formation. And when FSH was taken away, plaque formation went down. When FSH was reintroduced, plaque formation went up. Why does this occur? Well, FSH and the FSH receptor are found on monocytes in circulation, and monocytes become more sticky and adhere to endothelial surfaces in the context of elevation. And so, as we treat patients with a GnRH agonist or antagonist, and we may elevate FSH, that may be the mechanism by which we are inducing potentially a short-term cardiovascular morbidity and long-term effects, as I mentioned before.

So my topic is on choice of agonists—sorry, choice of therapy for ADT and ARPIs. And I think the evidence is pretty clear that the GnRH antagonist group of drugs leads to potentially a more favorable cardiac outcome for those with a history of CVD. And this was first demonstrated by Peter Albertsen 10 years ago in demonstration that LHRH agonist versus degarelix led to a 56% reduction in severe CV events or death.

And of course, this HERO study has been mentioned a couple of times in this meeting. A prospective study looking at the oral agent relugolix versus leuprolide. And in this population, there were a number of individuals who entered into this study with a prior history of cardiovascular morbidity. And in that group, there was a 54% reduction in the risk of major adverse cardiac events.

So I think the data are pretty clear that the GnRH antagonists are a more favorable therapy choice for men with a history of cardiac disease. But what about FSH? Well, it's quite interesting. FSH and LH both spike when you start the therapies. LH comes down, but FSH, at least in the HERO study, as was measured out to about a year, does begin a steady rise in the leuprolide arm versus the relugolix arm. So it may be that this is part of the backdrop. And again, these patients walk into our clinic with risk, and that further elevation of FSH may be part of the reason why these outcomes are seen.

And just to put a finer point on it, my recommendation is clearly with prior CV risk that you should choose a GnRH antagonist. And if you look at the odds ratio of a major adverse cardiac event, it's about 6 in the patients who have a prior history. And so we can debate this data, but I think they're emerging as fairly clear.

What about the androgen receptor pathway inhibitors? This morning I had “androgen receptor signaling inhibitors,” and I changed my slide to make it ARPI. So I'm sticking with that. And I think we all should. So what about ARPIs? Lots of retrospective data now—claims data—showing that men receiving ARPIs with prior CV risk have bad CV outcomes. And it's hard to tell looking at this. This was Grace Lu-Yao's data from a few years ago. It looks at the number of risk factors that men carry into their treatment experience and their likelihood of hospitalization. And of course, the greater the prior risk, the more likelihood of subsequent risk. Abiraterone may appear, at least on this analysis, to be slightly worse.

My group at the University of Minnesota assembled a series of questions on the MarketScan database in the United States. And we analyzed over 6,000 patients who received either abiraterone or enzalutamide. And in this analysis, we found that abiraterone comes with a slightly higher adjusted risk compared to enzalutamide when one looks at all cardiac morbidity, when one looks at other factors as well. Patients who come in with atrial fibrillation at baseline, older patients at baseline, higher CV risk scores are associated with more adverse events from abiraterone.

So why abiraterone and enzalutamide? Are they different? Abiraterone induces what I call the “abiraterone cardiac syndrome”: hyperkalemia, hypertension, heart failure, edema, and atrial tachycardia. And these things seem to go together. And this is a very nice graphic on the left here from a series of pharmacovigilance database studies which looked at the coexistence of these various phenomena in patients receiving abiraterone and their likelihood. Now in the graph on the right, you see that in patients who start abiraterone, the incidence of atrial tachycardia or heart failure—I don't know if it's quite a spike, but there is an uptick right after therapy starts within the first three months.

So this gets back to my point about an adverse event issue. Yes, in ADT you're inducing a long-term effect. But with abiraterone, for example, the effects can be immediate. And that's when they're under our care the most. That's when we are initiating a therapy. So these factors that Dr. Suter was talking about—the monitoring—all of that is completely and highly relevant in this setting.

Again, let's think about mechanism. Remember, abiraterone is co-administered with prednisone to reduce the mineralocorticoid spike that is induced. And from this, I pulled data from the phase I study of abiraterone that's now getting to be quite dated, published in 2010. But in that study, it was demonstrated that the mineralocorticoid precursors—deoxycorticosterone, which is a very strong mineralocorticoid, and corticosterone—actually go up thousands of fold over baseline levels. And these are strong mineralocorticoids. They lead to salt retention, hypertension, fluid overload, heart failure, et cetera.

That's why we administer prednisone. But prednisone may be not enough in all of these patients. And so we need to monitor for those things. If patients are developing that abiraterone cardiac syndrome, whether it's edema, et cetera, we should intervene with antihypertensive therapies, diuretics, perhaps other things as well. We clearly, as a field, need to approach the best and optimal way to treat hypertension in abiraterone and other settings.

Interestingly, abiraterone's cardiac toxicity is higher in the CRPC population by a lot compared to the hormone-sensitive population. And this was a very nice analysis that looked at the data from LATITUDE and other studies where you had a hormone-sensitive population versus the CRPC population. And it makes sense that a patient who has CRPC is going to, in fact, have other factors that they bring into the clinic, including a longer term of androgen deprivation therapy.

Very quickly, enzalutamide monotherapy still has something of a cardiac signal, as came out in EMBARK, and I refer you to that literature. Apalutamide and darolutamide—we know less about them. Interestingly, darolutamide has specific package insert language on ischemic heart disease, although the incidence doesn't appear to be higher than it would be with apalutamide—it's just different labels.

Was that for real? Was that a minute already? OK.

[LAUGHTER]

I thought you just bumped it. So finally, I'm going to just summarize that we have a number of factors that we should take into account as we go through choice of therapy. And I want to thank you for your time and attention, and attention to the panelists for putting this on the questions. Thank you.