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Charles Ryan: Hello. Today, I'm talking with Alicia Morgans, Associate Professor of Medicine at Northwestern University, a Medical Oncologist, and an expert on cardiovascular complications of prostate cancer therapy where she has recently co-authored a paper that looked not only at prostate cancer's risks, the cardiovascular risk of prostate cancer endocrine therapy, but also very nicely included a long section on breast cancer and breast cancer therapies and their implications for the heart. We're going to focus on the prostate cancer aspect of things for obvious reasons.

Alicia, tell us a little bit about this scientific statement from the American Heart Association. Why was it done? What was the purpose of getting it out there?

Alicia Morgans: Sure. Thank you so much for the invitation to talk about this. So I think the American Heart Association really wanted to jump into this realm because there has been an interest in cardiovascular complications as it associates with all hormonal therapies as they are applied to breast cancer and, of course, to prostate cancer for a long time. And certainly, there was a consideration of other GYN malignancies as well. And we just wanted to compile the data as it exists, to try to put forth a statement to help people understand how they might best move forward in clinical considerations. And there are definitely gaps in the literature, but certainly, to compile that information as it exists and then try to provide some guidance, was the goal?

Charles Ryan: Yeah. It's interesting. If you look at this paper and what was done was, breast cancer therapies were broken down into SERMs and aromatase inhibitors which I've always thought, selective estrogen receptor modulators and aromatase inhibitors, which, to me, have always been very analogous to your enzalutamide, as your AR-targeted drug and your abiraterone as your lag in production drug. But what's interesting in the breast cancer data is there are different risks based on the type of therapy. For example, venous thromboembolism is more common in the SERM group whereas hypertension, cardiovascular events and metabolic syndrome are more common in the aromatase inhibitor group. And what is your sense of if, as we think about prostate cancer, the differential risks when we break down ischemic heart events, hypertension, arrhythmias, et cetera, et cetera? Do we have a clear sense as to what therapies cause which risk, and when?

Alicia Morgans: So as a prostate cancer oncologist yourself, I'm sure you know we don't, and I think that the breast cancer community is actually quite far ahead of us in terms of understanding the basic pathophysiology of why these events are happening. The benefit that they have perhaps is that there has been a lot of evidence supporting the role of estrogen in the development of clots. And so when they are thinking about these differential mechanisms of inhibiting estrogen signaling, they could fall back on that evidence. But we, in the prostate cancer community, although we know that with our treatments like GnRH agonists and antagonists we do lower testosterone and, of course, subsequently lower estrogens. We don't know how that differential actually impacts the risk of a patient's likelihood of forming a clot or having other complications. There is some evidence between GnRH agonists and antagonists that, of course, we delved into in this particular guide, but we don't know anything to the level that the breast cancer oncologists know as to what you've alluded to.

Charles Ryan: In this paper, also in the prostate cancer section covering the cardiometabolic derangements of androgen deprivation therapy, it's almost made this seem, and I agree with this, this is kind of how I counsel patients, is it's really all about the metabolic syndrome. The lipids, the glycemic control, the body mass index, the decrease in the lean mass, and the increase in fat mass, and that perhaps all other risk factors fall out from there. So what do you think, and what do you counsel patients about these risks? Are these drugs directly toxic or if a person takes one of these drugs and I'm talking now about the orals, we'll come back to the GnRH situation. But if a man is taking enzalutamide or abiraterone or darolutamide, are these drugs directly cardiotoxic? Or if that person does not develop metabolic syndrome, are they essentially protected from those risks?

Alicia Morgans: So I would say it's definitely not all about metabolic syndrome. It's not all about changes in cholesterol. It's not all about changes in adipose tissue or loss of lean muscle mass or even diabetes or insulin dysregulation. I mean, this is very clear, from my perspective, a constellation of symptoms that comes together over time and actually, very interestingly, seems to be a relatively early acting event that after you initiate GnRH agonist therapy, for example, within the first year we can see that over 5% of patients, even when we exclude the highest risk patients who are likely to have cardiovascular complications, these patients seem to develop these major adverse cardiovascular events, so things like heart attack and stroke. So it's very clear to me that it is an early event, but also an event that is not necessarily predicated on cholesterol levels or anterior-abdominal adipose tissue, but it's really more complex in some metabolic milieu that may predispose patients to develop these adverse events.

Charles Ryan: So what you're saying essentially is although we should, of course, monitor and manage our patient's cardiovascular risks, we should know about them. Even if we do that in a perfect setting, there may be a risk above and beyond the known risks, so to speak, the known mechanisms, so to speak.

Alicia Morgans: I would agree with that a hundred percent, and I think that any time we have reversible risk factors, things like blood pressure, cholesterol, these kinds of things or certainly anything to do with blood sugar, we should try to intervene on those areas and try to make that patient as whole as possible in terms of reducing cardiovascular risks. And I think that is something that we do not always do as an oncologic community. We are very focused on trying to ensure that we have good cancer control, but this does require that we collaborate with our primary care partners and certainly our cardio-oncologist and our cardiologist to make sure that we have all of these risk factors tidied up and addressed as we continue to really ensure that we have holistic care of our patient and reduce the risk of complications of their therapy in addition to ensuring that they have good prostate cancer control.

Charles Ryan: Let me tease out something else that you said which is, you said you think that this may be an early event factor, when people start therapy, that cardiovascular events are likely to be early on. This, if that is true and the data seem to suggest that may, in fact, be true, then it negates the argument that we should use, for example, intermittent hormonal therapy or other approaches to stave off some of the cardiovascular risks. Is that a fair assessment?

Alicia Morgans: I think it's a great question and not a question that I can answer right now, because I don't think we have the data that really clearly explains what is happening or what the underlying biology is. We do know from a SWOG study on intermittent therapy that there was a higher risk of cardiovascular and thrombotic complications associated with intermittent therapy as compared to continuous therapy in this population. And so, does that mean that there is some risk associated with starting and stopping androgen deprivation therapy? I don't know, but I definitely wonder about that, and I do think that further evaluation of what the underlying biology there is, is absolutely warranted.

And this is something that I've been curious about for a few years and perhaps maybe mitigated by using things like GnRH antagonists though, again, that's another area, we don't know the answer there. So is the answer continuous therapy or is the answer intermittent therapy with the GnRH antagonist? Either of those could be possible. We don't know the right answer, but I think there is so much to dig into in this area. And it is definitely, I think in the clinician's best interest to try at least to reverse those reversible risk factors in terms of cardiovascular disease and ensure that patients have their feet planted in the best setting that they can be as they are getting this therapy.

Charles Ryan: Mm-hmm (affirmative). Mm-hmm (affirmative). Clearly. And so, this issue of the GnRH agonist versus antagonists, walk us through a little bit about what we know. Are we close to settling that discussion about which approach would be superior in terms of cardiovascular risk?

Alicia Morgans: So another great question and not necessarily one that is answered or could be answered by me or by the American Heart Association guidelines. I think that we acknowledge that there is an apparent difference both in the phase two data that is available from injectable GnRH antagonists from the past and in the oral GnRH antagonist that was recently approved in December 2020, relugolix.

Again, I don't know the answer here, but I would say that this is an area of active investigation and not an area where we have a clear and defined path forward. But if I have a patient who has a very high cardiovascular risk, at the get-go after initiating therapy, I definitely think about using a GnRH antagonist as a potential way to give them prostate cancer control without giving them increased cardiovascular risk. This is a decision that I make as a clinician and not a decision that I make necessarily based on firm data that tells me there's a clear difference. Although, of course, in the HERO trial, there seems to be a pretty clear distinction. This is one trial and is an addition to our armamentarium of information. But I would say this is still an area of active investigation and until we understand the biological underpinnings of this, we are still sorting it out.

Charles Ryan: So in the HERO study though, patients with a recent history of cardiac events were excluded from the study. So we really don't know much about what to do with patients with more recent cardiovascular events and whether that benefit passes onto them, correct?

Alicia Morgans: That's true. Actually, patients who had had a recent cardiovascular event, major cardiovascular event, including some sort of stroke or thromboembolic event, or certainly an MI were excluded if they had had this event within the preceding six months. And those patients who had had any kind of event in their past and who knows at what timeframe they had that, were included. And it was interesting that they had a significantly increased odds of having a cardiovascular event when exposed to a GnRH agonist, in this case, leuprolide versus a GnRH antagonist, relugolix. I don't know for sure that it's leuprolide that adds that risk or if it's the mechanism of action, the GnRH agonist action. And I would favor that it's probably the mechanism of that drug, not the specific drug that does it. But importantly, there was an increased odds of a cardiovascular event and if we use the GnRH antagonist we may be able to decrease the risk for that patient population.

Charles Ryan: Yeah. As we've discussed before, it's interesting, cardiac myocytes may actually have receptors for GnRH on them and there may be a situation where activating that through an agonist may destabilize a plaque or something along with those events, precipitating those cardiac events. Still, a lot more to learn on this topic.

One question that I've always had is, I was always struck by the intermittent versus continuous study in patients who had progression after radiation. It was published in The New England Journal of Medicine by Juanita Crook and in that study, there was no difference in survival. But in the continuous arm, the patients who received ADT continuously were more likely to die of cardiovascular disease than prostate cancer. And in the intermittent arm, they were more likely to die of prostate cancer than other causes. So what that tells me is that maybe what we should do is treat everybody with continuous hormonal therapy but we should try to mitigate and maximize our control of their cardiac risk factors. Because in that scenario, if we can reduce the risk of death from cardiovascular disease, there would have been an overall survival advantage in favor of continuous therapy. Does that make sense to you and how do you interpret those data?

Alicia Morgans: So it absolutely makes sense to me and it also makes sense in light of the SWOG data where they looked at intermittent androgen deprivation therapy and also found that there was an increased risk with the intermittent administration of GnRH agonist therapy of thromboembolic and cardiovascular events. And so I guess my take is, agreed, we should try to make sure that we minimize these cardiovascular risk factors that are reversible because that will reduce the risk of cardiovascular events in patients that we are treating with continuous androgen deprivation therapy. Absolutely. But the question is, what is the underlying biology that is causing this difference? And what about starting and stopping GnRH agonist therapy, if it puts patients at particularly increased risk? Is it something to do with activating platelets? Is it something to do with that direct GnRH agonist activity on a receptor, a GnRH receptor that's perhaps on vasculature or myocytes or somewhere else? Maybe even platelet activation, as I mentioned, that is causing these events to happen.

We don't understand. There is so much that we have to dig into here, and this is an area that I'm actually very excited to explore. But in terms of giving good clinical advice, I would say we always just have to reverse those reversible risk factors, optimize our patients in terms of blood pressure, cholesterol management, and diabetes or glucose management. And if we can do all of those things, we just have to, fingers crossed, hope the patients do not develop these complications and potentially use medications to provide androgen deprivation therapy that is going to be the lowest risk options for those patients, and perhaps that is GnRH antagonist therapy. But I would say there is a whole lot of biology for us to still dig into and to understand in this realm.

Charles Ryan: Agreed and an excellent answer and a very thoughtful one. One final question is, this paper also alluded to racial and ethnic differences in CVD risks in both the prostate cancer and the breast cancer populations. Briefly, what do we know about those differences in risk in these patient populations?

Alicia Morgans: So it was interesting. We actually had quite a bit of debate as a team on this. We usually don't have a lot of information on racial differences in prostate cancer patients in terms of their cardiovascular risk when they're exposed to lots of different therapies or any therapies, really. So I think that what this raised for us was a clear flag of a lack of data and an understanding that we do need to dig into the racial differences that may exist in these patients that we take care of on a day-to-day basis. As we treat them every day with treatments to lower their testosterone, is there perhaps a heightened or a lesser risk in different racial groups? We don't know. And so, it is our obligation to understand this better and to really provide the best care that we can to every patient regardless of race or where they are from, geographic origin, and part of that revolves around us, understanding things by doing more research and getting the data.

Charles Ryan: Very good. All right. We will look forward to seeing your name on some of that new research as it comes out over the next few years. Always a pleasure to talk to you, Alicia. I want to thank you for your leadership in this discussion for us as a field and your participation in this project with the American Heart Association. It's really important. And even when you think about it, the second leading cause of death in men with prostate cancer is a cardiac disease and there are studies where, as you alluded to, where the risks of cardiac disease and morbidity and mortality even approach that where if we could correct those risks, we could see greater improvements in some of our therapies that we are studying. So it is a really important area for us as oncologists and urologists to treat this disease, to be thinking about, and to partner with primary care doctors and cardiologists alike. So thank you, Alicia. Any final statements on this important paper?

Alicia Morgans: I would just say that I think from the AHA's perspective, and I am certainly not speaking on their behalf, I am certainly just a member of the committee that participated in the construction of this paper, that we should do whatever we can, as clinicians who are treating patients with prostate cancer, to reduce the modifiable risk factors that we can. So that means paying very close attention to things like blood pressure, cholesterol, and diabetes or blood sugar control, and to partner with our primary care doctors, our cardio-oncologists, our cardiologists, our endocrinologists, whoever it is that we need to partner with to ensure that these factors are optimized so that patients who have cancer, prostate cancer in this case, can actually receive the therapies that they need for optimal disease control while also maintaining and optimizing their cardiovascular and blood sugar control as well.

Charles Ryan: Thank you very much.

Alicia Morgans: Thank you.