Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to start today a round table discussion about cardiovascular health and men with prostate cancer treated with androgen deprivation therapy. I have multiple colleagues here with me today, so let's go around and introduce them. First, my co-moderator, Dr. Mike Cookson.

Mike Cookson: Hi, Mike Cookson from the University of Oklahoma. I'm the Chairman at the Department of Urology in Oklahoma City and I also serve as President of the Society for Urologic Oncology. A pleasure to be with you today.

Alicia Morgans: Thank you. Next, Dr. Bertrand Tombal.

Bertrand Tombal: Hi, I'm Bertrand Tombal. I'm a urologist from Brussels, Belgium with a specific tropism for hormone therapy.

Alicia Morgans: Wonderful. Thank you, Bertrand. And finally, our cardiologist, cardio-oncologist, Dr. Javid Moslehi.

Javid Moslehi: Hi, my name is Javid Moslehi. I'm a cardiologist at Vanderbilt and I have had the pleasure to work with many oncology colleagues over the last decade in this new field of cardio-oncology among them being many of our prostate cancer colleagues, including Dr. Morgans.

Alicia Morgans: Great. Well, thank you all for being here. I'll just start off our conversation with the first question and that is going to be really to Dr. Cookson, who as a co-moderator, I know you've been watching all of the presentations by the esteemed faculty that we have here. And I know you treat a lot of men with prostate cancer. When you think about the cardiac risk of these patients, how do you think about that in terms of the risk for any individual? Are there some patients that you really do think are at higher risk, as we heard in some of these presentations? Or do you see all patients as really being equal in this?

Mike Cookson: That's a great question, Alicia, and I want to say I'm probably the first to admit that I haven't done as good a job on this as I should have. I think that urologists that are caring for men with advanced prostate cancer are under a lot of pressure to do the right thing. And that means from assessing the patient, staging the patient, incorporating the treatment algorithms, and what's the right fit... Then you throw in genetic testing and we now have this, I think really a renaissance in the understanding that there is cardiovascular risk here. We haven't done a good job of assessing the baseline risk factors in addition to assessing maybe even baseline laboratory testing with those men prior, too. The field of cardio-oncology is new, I think, and not very well developed. And so I think there's a great opportunity for us to really come forward with better tools for the urologist so that they will understand those risk factors of the men prior to the treatment and then perhaps interventions to mitigate some of the risk as we go forward.

Alicia Morgans: That's great. And I think that, like you said, cardio-oncology is a field that has only been around for, I would say maybe a decade or so, maybe a little longer, but it's definitely infiltrating into different practice areas and it's not as widely disseminated as certainly as things like urology, which has been around for a long time. Dr. Moslehi, as a cardio-oncologist who's been sort of integrated into the GU oncology program and actually several other cancer sites, just given the risks and the therapies that we use, how would you recommend to others that they think about really having a partnership between cardiology and urology or medical oncology for that matter as we try to optimally care for these patients?

Javid Moslehi: Yeah, really great point. I think there are a couple of steps that are absolutely important. One thing we know about cardiovascular disease per se, like heart attack, heart failure, they just don't happen suddenly and out of thin air. Many times you build cardiovascular risk and attenuating and addressing these cardiovascular risks can decrease the risk of cardiovascular disease later. And I think at least with the prostate cancer space, one of the things that is absolutely critical is what is the baseline cardiovascular risk in any patient? And how can we attenuate these? And I think the ABCD steps that we have now through the NCCN is one step toward that.

I think the other thing to recognize is that we're actually in a good spot. There was no need for cardio-oncology 20 years ago because cancer patients weren't supposed to do well. But because of the team approach that you and the field of prostate cancer have brought on, where radiation oncologists, urologists, and an oncologist work together, there have been improvements of care. You're not going to suddenly die of your cancer anymore. And these other pertinent input issues become important. And I think building on that team concept again, the integration of a cardiologist or a cardio-oncologist in the high-risk population becomes absolutely paramount, especially in the coming years.

Alicia Morgans: Great. I completely agree. And I have a question around that to Dr. Tombal, who I know has been so engaged in understanding the biology behind cardiovascular risk, the different approaches to therapy, and as you see this new potential opportunity in relugolix and certainly in degarelix, which we've had for some time now, do you think that there will be a patient that you see in clinic that you're going to be more likely to use these GnRH agonists in? Or do you feel like things have been just fine? And we know that we've done our best for our patients, but we do have new information now. Will that impact your treatment decision making in your clinic when you think about these options?

Bertrand Tombal: I think in Europe overall, degarelix is doing much better than in the US. If we look at the population of patients with cardiovascular disease, most of them are receiving already an HRH antagonist. The problem of degarelix is that it's not easy to handle. It's a monthly depot so many people don't see the benefit, but actually, it is already implemented. We started looking at cardiovascular disease through actually the exercise thing. We started having a recommendation on putting everybody on an exercise training program, resistance training exercise, six or seven years ago. It's pretty common. It's now recognized by the EAU guidelines and more and more urologists are paying attention to that because I say, it's not different that if you have to do a prostatectomy of a TURP. If you have somebody on a Plavix® or somebody on one of the new anticoagulants, you're not going to throw the patient in the OR and start cutting in it, you know that you're going to be in deep trouble.

The message was you should basically regard people, you will start ADT as any other people you will do surgery because then you start understanding the risk and the message went through. And also more importantly, actually for cardiovascular prevention, the best hormone therapy is no hormone therapy at all. There was a lot of reconsideration of not using ADT alone, of using ADT only in high risk. I think that, yes, the message has been percolating and more and more urologists are looking kind of with more attention to that.

Alicia Morgans: Great, thank you. Now I know Dr. Cookson, I know you had some questions that you wanted to pose as well.

Mike Cookson: Yeah. Thank you very much. I'll ask Javid first. We know that there are these competing risks of heart disease, probably equally a killer of men with advanced prostate cancer as prostate cancer itself. What type of things should urologists be doing in terms of referral and interventions to try and mitigate the cardiac risks in the setting where they're sort of compelled to treat the cancer?

Javid Moslehi: Yeah. This is a great question because obviously if you want to send every prostate cancer patient to a cardiologist or a cardio-oncologist, we would simply get overwhelmed with the number of patients. I think the biggest issue to ask as a urologist and the first kind of dividing and important question is, have you had cardiovascular events, yes or no? Have you had a heart attack? Have you had heart failure? Have you had arrhythmia? Something that's very kind of concrete in terms of cardiovascular disease. And I think those patients should be referred to a cardiologist. I think immediately recognizing that there is this big divide with baseline cardiovascular risk factors, I think it becomes important. It also becomes important, I should add for the surgery part. You don't want to take a patient who had two stents placed a couple of months ago. You want to get a cardiac clearance.

But I think also the important responsibility is upon the cardiologists to have a better understanding of the different treatments on the oncology side, between surgery, between the different hormonal therapies and can help guide with respect to assessing these risks on the patient. I think the second step beyond whether you do or do not have cardiovascular disease is cardiovascular risks. Things like diabetes where you don't quite have disease yet, but you clearly are on your way there: hypertension, hyperlipidemia. And I think that can be a combination of efforts between the oncology team, primary care team, and potentially cardiologists. But that immediate risk stratification, in my opinion of those with baseline high risk, becomes really important. And the simple question of yes or no, have you had cardiac disease per se? Can be very helpful.

Mike Cookson: It looks like that would be a pretty good algorithm to sort of assess those patients with that risk and send them sort of immediately to get the cardiology consult. What about the cumulative risk? Because we saw in the data that you presented that there's sort of this early effect that happens, but then cumulatively, many of these men are living longer, years, and we hope they will go more than five to 10 years on these treatments that are suppressing their cancer. What are the cumulative risks that are going to occur? And when do they flip to needing to see the cardiologist?

Javid Moslehi: Absolutely. I think one of the key points that we have learned through 50 years of cardiology trials is attenuating and addressing risk factors matter for the patients. If you check the cholesterol and start somebody on a statin early, we have tons of data suggesting that there is this distinct risk between the patients. Addressing and attenuating these risk factors become important. And I think the question is who should be responsible for it? Who should be the person starting the patient on a statin? And I think during this prolonged period where we're seeing patients again, addressing and controlling those risk factors become important. Every group has to assess, well, should it all be cardiologists, or are the cardiologists simply going to get overwhelmed? Combination of primary care versus cardiologists? Or it could be a nurse practitioner, a strength being among the work teams, especially in the tertiary care center. I think the biggest question is not, I think we know what to do, it's how we do it in different healthcare delivery models.

Mike Cookson: Yeah. Thank you. And Bertrand for you in the United States, the GnRH agonists and the antagonists have not been as widely adopted as what you're suggesting in Europe, do you believe that with the use of this new oral agent, that there will be opportunities for widespread usage instead of just really the occasional use?

Bertrand Tombal: I think yes because we're discussing the cardiovascular risks, but there are other benefits. I would say, especially for all these groups of patients, you receive short-term hormone therapy like an adjuvant or an external beam. We treat more and more oligometastatic patients. There is a very rapid recovery of testosterone. I'm guessing that's going to be quite successful because that's, look it's like enzalutamide and apalutamide and darolutamide, they're so easy to handle, that that's probably is going to be a very good drug to use. Easy to use.

Mike Cookson: Bertrand, you have an understanding, or I'll ask Javid too, in the patients, let's say they go on treatment for a year, or it's in combination with radiation therapy and they come off. Are those cardiovascular side effects that we've seen traditionally, are they reversible? Or do they persist?

Bertrand Tombal: That's a $1 million question. Actually, what we know is that in contrast to what we've been believing, the opposite is happening. If you put these patients on intermittent, every time you restart the treatment and Maha Hussain has done a beautiful analysis by matching the patient in his trial, vis-a-vis Medicare patient and you increase the risk every time you restart. That, I don't know. Do you switch the patient to a baseline, a higher risk whether it comes back to normal? I have absolutely no idea.

Javid Moslehi: I wanted to make one more comment if that's okay. I think I mentioned there are common risk factors for the cancer and cardiovascular and I think what that potentially could speak to is that some of these standard cardiovascular risk factors that we think of like hyperlipidemia could be a risk factor also for the cancer and the cancer growing and that extends to diabetes. And we already have some intriguing data.

For example, Phil Kantoff's group had a very intriguing paper in JAMA Oncology a few years ago where although this was a retrospective analysis, patients who were on a statin did better for their cancer issues and forget about the cardiovascular issues than those who were not doing a statin. This argues, although it doesn't, the potential that statins beyond the many great cardiovascular benefits, may have some beneficial effects on the cancer and cancer growth itself as well. And I think this is the kind of thing we may want to think about. And I think if this concept is true, it has huge implications for, really, the health of all of our patients, both from the cardiovascular side, but also for the oncology side.

Bertrand Tombal: In this regard, I have a quick question for you, because many time we asking the question for all of these patients we put on long term ADT, who are already not working out a lot, kind of a little bit of obesity already, a little bit of hypertension, is there a role to put them systematically on metformin because actually metformin, we have made the similar observation and there is actually an arm in the large STAMPEDE trial looking at the benefit of metformin and people believe that the benefit on OS could be a mixed benefit between a so-called anti-cancer activity and a CV protective activity. I'm thinking, especially about all these patients who don't want to exercise, is there any interest to put these patients on metformin?

Javid Moslehi: Absolutely. Really great point. I think we have some retrospective analyses suggesting metformin can be beneficial from the prostate side, but I think the other important thing to see is these are retrospective studies, but I think it is time now to do such an intervention study and looking at metformin and as you correctly pointed out, my understanding was that there were a number of studies looking at metformin effects in patients. I think that concept while very intriguing with the buildup of retrospective studies, I think it is time to answer that in a proper prospective intervention study. And I think this is true with metformin, but I'm going to also bring in another intriguing thing. I mentioned this fact that you lose fat and you very nicely pointed this out, you lose muscle and gain fat with ADT. Well, what if we could have our patients intervene and use basically exercise and not just any old exercise, but exercise that builds muscle. I think that's another thing that we could potentially prescribe to all of our patients with this. But I think also something that can be tested in a proper prospective trial.

Alicia Morgans: Bertrand, do you have a comment on that? Because I think that you mentioned that you are in Europe, really it sounds like prescribing exercise and physical activity for patients. And I know there are some trials that are specifically looking at this. Small Phase II here in the US, but is this something you're already integrating into practice?

Bertrand Tombal: Yeah, yeah, since 2007, we actually have patients get nine sessions reimbursed with a physiotherapist and we have a whole network of what we call "exercise therapists", and they usually get a mix of resistance training exercise and aerobic exercise. It's also extremely popular in Australia and also in the UK. This is something that's getting really common for these patients because on top of that, it's extremely good for depressive mood, humor, bone loss. It may tackle a lot of the side effects.

Alicia Morgans: Absolutely. We'll have to see if there's a way, we'll talk offline to really see if we can match institutions that are doing this versus not doing this and actually a comparison of that data. Of course not randomized, but maybe we could do something like that because demonstrating that is probably the way that we could also get that here in the US because that's a hard thing to overcome. It's not just a pill you take when you wake up. And the more data we have to talk with our patients about, the more eager and enthusiastic I think they'll be.

And as we start to wrap up, I just want to ask one last question of Dr. Cookson. I know you do treat patients with metastatic CRPC, so the more advanced patients who often are receiving oral agents like abiraterone or enzalutamide, these oral androgen receptor-targeted agents, which we know from some studies at least, there's a suggestion of some increased cardiovascular risk, particularly in patients who have a history of cardiovascular disease when taking those therapies. What are your thoughts about the combination of these therapies with traditional GnRH agonist therapy, which is usually what we're using when we are making those assessments about increased risk? Versus using things like degarelix or relugolix if it's available at some point that may have a lower risk than the agonists?

Mike Cookson: I think you just described the next study that needs to be done in metastatic-castration resistance because those men all lead in with years of ADT exposure. Usually in the US, that's traditional agonist exposure. Whatever we knew from the baseline studies of the HERO trial, you could imagine taking those baselines now compounded cardiovascular risks onto additional therapies. Not only do they potentially have more of this biologic that we don't understand how that cardiac disease is compounding, but they're also more fatigued. Their ability to exercise is going to be less, their ability to move. And they've already lost that muscle mass due to years of exposure. I think it's a great question that I don't have the answer for, but I fear that the cardiac risks are higher than we ever really anticipated.

Alicia Morgans: Great. Well, we'll have to continue to discuss this. We are out of time at this point, but I want to thank all of you for your willingness to talk about these issues that are so important to men with prostate cancer and those that care about them. Thank you so much for your time.

Javid Moslehi: Thank you very much.

Bertrand Tombal: Thank you.

Javid Moslehi: Thank you, guys. Thank you again, everybody.

Mike Cookson: Thanks for the great presentations.