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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm a Professor of Medicine in urology at Tulane University and Medical Director of Tulane Cancer Center. I'm delighted to be joined here today with Alicia Morgans, who is at Northwestern University and has so many titles, they are hard to remember. So with that being said, I get to ask her the first question. Alicia, I think we understand a lot about prostate cancer and you and I spend our lives thinking about prostate cancer. That being said, what about cardiovascular issues in these patients? How prevalent is it? How important is it?

Alicia Morgans: Yeah, so thank you for asking that question, Oliver, because I think we, as medical oncologists, as urologists, need to really be cognizant of the fact that so many of our patients actually have cardiovascular comorbidities. I would say there is a range in different studies. There was some data that came out related to patients who were starting on the standard of care, abi, and enza, for example, and in that population, two-thirds, or, about 67% seemed to have cardiac comorbidities. In the HERO trial that was recently reported, looking at men who are being treated with relugolix, they actually excluded men who had had a cardiovascular event within the preceding 6 months. Despite that, when they looked at risk factors for cardiovascular disease, including hypertension and obesity, about 90% of people seem to have some cardiac risk factor or something that they could link potentially to increasing the risk of cardiovascular disease.

I think in general, as we consider the aging prostate cancer population, where we know that increasing age is a risk factor, of course, and being a male is a risk factor for prostate cancer, these are actually some of the driving risk factors for cardiovascular disease as well. So we, as oncologists, as urologists, need to be aware of this, and then counsel our patients, particularly as we start medications like androgen deprivation therapy and our intensification strategies that actually increase the risk of cardiovascular complications as well.

Oliver Sartor: Well, let me ask you to explain that a little further if you don't mind. How does low testosterone translate into higher cardiovascular risk? How does that occur?

Alicia Morgans: Yeah, so on a very basic level, we've known for a long time that low testosterone can affect cholesterol levels, for example, where we see actually increases in total cholesterol, triglycerides, we actually see increases in HDL as well, which is our good cholesterol, but that is not enough to offset the complications from the other forms of cholesterol that are increasing. We also know that we see increased waist circumference associated with androgen deprivation therapy and low testosterone, loss of muscle mass. These are also potential risk factors for cardiovascular disease.

There is some sense too, that we may be causing some disruption in cholesterol plaques by having low testosterone or some change in the rigidity of the vasculature and things like GnRH agonists may actually have direct effects on myocytes that are still being evaluated. So, it's not just the low testosterone that increases or alters these risk factors.  And I didn't mention insulin insensitivity, which has also affected, but also maybe even some direct effects on the vasculature and on myocytes related to the drugs that are inducing this hypogonadism.

Oliver Sartor: So we've got cholesterol, we have potential diabetes, glucose tolerance, we have obesity, and one of the things, of course, I've noticed in my patients is they are less likely to be out exercising, unless I encourage them to do so, often associated with a little bit more fatigue, a little more nurture if you will, more likely to be a bit of a couch potato. So lots of factors where the low testosterone contribute to the risk factors we associate with cardiovascular disease.

Okay, so now we're going to move forward and say, the population that we treat is affected by a variety of cardiac risk factors. The treatments we give are associated with an exacerbation of those risk factors. So, what can we do to begin mitigating these risk factors in the patient we treat? Because it really is an important issue. Not everybody dies with prostate cancer, and in fact, there is cardiovascular mortality as one of the most important non-cancer issues that we have to deal with.

Alicia Morgans: Absolutely. It's actually the leading cause of death among male Americans at present, and among men with prostate cancer, it is the biggest competing risk, the biggest cause of mortality other than cancer itself. So it is absolutely something that needs to be addressed. I was fortunate to participate in these efforts, but a group a few years ago put together an ABCDE thought process or algorithm to consider how we might counsel our patients related to their cardiovascular risk.

"A", of course, is actually awareness. Just being aware that we are affecting these risk factors and that patients are at risk, I think, is critically important. "B" is blood pressure and monitoring and making sure that patients have good blood pressure monitoring and control, particularly when they are on intensification strategies like enzalutamide, and abiraterone, that might actually cause an increase in blood pressure, and so it is something that we need to be aware of. "C" is cigarette smoking. We know that cigarettes and smoking can certainly increase the risk of cardiovascular events, so cessation, at any point, if possible, if patients can do it, is always important.

"D" is both diabetes and diet. So attending to blood sugar, and also using a good heart-healthy diet, which is low in saturated fats, high in things like vegetables and lean meats, is a great way to make sure that we are lowering our risks. And then of course paying attention to and screening for prediabetes, diabetes, not necessarily in the urology clinic or the medical oncology clinic, but partnering with primary care and with patients so that they are aware that their blood sugar may be affected as well. And finally, "E" is exercise, which, as you said, is something that is probably one of the hardest pieces to get in, because patients do feel fatigued. But there are so many benefits to exercise, including increasing their energy if they are able to do it, getting off the couch even to walk, but we also know this helps bone health and is generally just such an important part of keeping patients feeling as well as they can. So, ABCDE is the algorithm that I try to follow.

Oliver Sartor: Yeah, and I really like that, and I can even remember it when I look at "ABCDE". But what about the drugs we use? Let's talk about the LHRH agonist, antagonist first. I realize this is a short program, but just a brief overview, and particularly maybe emphasizing some of the new oral and injectable antagonist data.

Alicia Morgans: Sure. I think we've known actually for a number of years that GnRH agonists may be associated with a slight increase in the risk of cardiovascular incidents and disease. This was actually added to a label that was guidance or warning many years ago. This guidance or warning was actually not added to the GnRH antagonist that we've had, degarelix, because there was not a clear association with that particular product.

What we saw in the HERO trial most recently, maybe almost a year ago, I guess, at this point, was that in this prospective phase 3 trial in which cardiovascular events were identified as a key adverse event of interest and followed prospectively for comparison, there was actually a lower rate of major adverse cardiovascular events in patients treated with relugolix, the GnRH antagonist, as compared to patients treated with leuprolide, a GnRH agonist. And really, the risk was about half when they were treated with an antagonist, and the difference in the risk was the most pronounced among patients who actually had cardiovascular risk factors or history prior to initiating treatment. So those patients at the highest risk actually seemed to have the most benefit.

So, there does seem to be a difference between the agonist and the antagonist in terms of cardiovascular risk, and this is a story that I would say we need to continue to monitor, watch, and see develop. But I think that risk is real, at least based on that prospective phase 3 study that really gives us our best evidence.

Oliver Sartor: We're going to move away now from the GnRH, LHRH story and move into some of the novel hormones, and I'll say enzalutamide, apalutamide, darolutamide, abiraterone, and again, we obviously don't have all day, but give me a little bit of a synopsis regarding these newer androgen axis-targeted agents and how you might think about cardiovascular risks associated with those new agents.

Alicia Morgans: Sure. Well, I think we have the most data on abiraterone and enzalutamide, and so the majority of risk has actually been defined with those two agents. Abiraterone sometimes can cause some fluid retention, which can exacerbate heart failure issues. Although, if we're monitoring closely and working with a cardiologist if a patient's on a diuretic, this can be mitigated. But both enzalutamide and abiraterone have been looked at, in retrospective data sets, at least. And for patients who have pre-existing cardiac complications, it was interesting. The risk of mortality for patients and the cause of the mortality, it was all-cause, so not cardiovascular-related, for patients who had preexisting cardiovascular disease when they were treated with these agents was higher than patients who did not have preexisting cardiovascular disease treated with these agents.

So, there is something about cardiovascular risk, particularly with these two agents it seems, that does come out of these data sets. These are not prospective studies though. And I have to say, I've used these drugs a lot, we all do for our patients or with our patients, and I think that one of the reasons that we see the signal with those two drugs is that we actually have the most data with those two drugs. This is not to say that there are no complications related to apalutamide or darolutamide, we just don't actually know. And so I think continued data analysis, and also prospective studies that are specifically assessing cardiovascular complications, are going to be important as we continue to understand and define those risks.

Oliver Sartor: All right. Very well-said, very succinct, and I agree completely with your statements. We have a lot more to learn despite the fact that we've already run a number of large trials, but there is more maturity within the abiraterone, enzalutamide data. And I think as the other ones are developing, there is going to be close scrutiny of this variety of endpoints, simply because they are important for men.

Now let's talk about drug-drug interactions. One of the things that we do quite often have to deal with things like anticoagulants, anti-lipid agents, the anti-hypertensives. What about these drugs in regard to drug-drug interactions? I wonder if you might have any comments here?

Alicia Morgans: Sure. Well, these are always something that we have to pay attention to, and I'm always grateful to have a pharmacist who, when I write a prescription will say, "Hey, I know you're trying to prescribe agent X or Y for your patient with prostate cancer, but he's actually on warfarin or he is on some statin or some beta-blocker, and that is going to actually be contra-indicated if you want to add this additional agent." So, being attentive and aware of that is going to be really important. And because so many men are on things like statins and some are on things like ELIQUIS® or other blood thinners, we need to just be aware that there are going to be these interactions.

Now, from what my limited experience with darolutamide has been, it does seem to have fewer, at least listed, drug-drug interactions. That being said, we can often find a way, if we have a particular agent that we really want to use and a really good reason behind it, we can often find ways to sometimes work with cardiologists or other physicians who are prescribing drugs that may have these drug-drug interactions. But I think the bottom line is, we just want to make sure that we identify them as we are starting these agents, because there can be these interactions, they can be potentially dangerous, especially if we are thinking about things like blood thinners or agents that may affect heart rate or blood pressure that we just want to make sure we understand, and we're doing all of this with the greatest caution.

Oliver Sartor: Well, listen, I think this has been terrific. We've talked about the population at risk, we've talked about androgen deprivation generally, we've talked about antagonists and agonists, we've talked about new drugs, we've talked about drug-drug interactions. Are there any other issues that you feel like we ought to address in the context of this discussion before we wrap up?

Alicia Morgans: The only final thing I would mention is that we really need to continue to talk to our patients. We need them to be their own best advocates. Sometimes that means engaging their caregivers, their loved ones, their children, whoever it is. But we need to make sure that men and their families are aware that these are real risks and that we care about their hearts just as much as we care about their prostates.

Oliver Sartor: Well, that's a wonderful ending statement. Thank you, Alicia. That was fun, and I learned from you and your experiences and thank you for your authorship on a recent important paper that, I think, helped form the nidus for this conversation.

Alicia Morgans: Thank you so much.