Michael Cookson: Thank you very much, Dr. Michael Cookson here from the University of Oklahoma. I'm a Professor and Chair at the Stephenson Cancer Center, and I'm also the President of the SUO. I appreciate the opportunity to be with you on this exciting conversation regarding some of the complications of ADT. My first question is for Dr. Matthew Smith. When you presented that very nice talk, it reminded me that we're a decade later on some of these sentinel reports from the American Heart Association and the warnings from the FDA. Do you feel that in clinical practice we are doing all we can to really improve the cardiac health of men on ADT?

Matthew Smith: I think the big picture answer is no. I think the similarity of the conclusions of my presentation and the American Heart Association Science Advisory of 10 years ago is understandable in that, if the effect of ADT with GnRH agonists on cardiovascular disease risk, if it is causal, is probably a modest effect. And so I think of it in three ways. One is we need to think about the overall health of our patients in making a decision about whether to treat with ADT or not. So a patient who's older and frail and likely to die of cardiovascular disease may not need aggressive intervention for his prostate cancer.

Second, is it's a teachable moment, meaning that in order to have the patient have the best long-term cancer outcome, we have to make them aware about the rest of their health. So for every patient I'm starting on ADT, I'm going to talk to them about risk reduction for cardiovascular disease risk, or for that matter at prostate cancer diagnosis, we're talking about that. And then third for the individual patient, we have to decide whether the treatment we're applying is going to meaningfully alter their risk.

Michael Cookson: And then I was impressed with some of your distinctions between the randomized trials, where many patients with significant cardiac disease are sort of excluded from entry. But I wanted to know given some newer data that's come forward, how do you kind of gauge the risk with the agonist, the antagonist, and even orchiectomy? Are they all equal or do you think there are differences there?

Matthew Smith: Well, I think this goes back to the days when degarelix was developed and there were some post-hoc analyses done of those randomized controlled trials that were suggested that there might be less cardiovascular risk. The problem, those were truly post-hoc and the quality of the analysis was let's say, challenged. But with the development of a newer oral GnRH antagonist, with the recognition of that issue, cardiovascular outcomes were prospectively defined and evaluated. Although it's worth noting it was not the primary outcome for the study, but the observation that there were fewer cardiovascular events with the oral GnRH antagonist, I think is consistent with prior data and really does suggest that they may be safer from a cardiovascular risk profile.

Michael Cookson: Okay. And I have a couple of questions for Dr. Ryan. I really appreciated your concluding slide, revealing the naked underbelly of some of the complications of the ADT. But I wanted you to comment on, you spend a lot of time on internal medicine questions and training, but many of the ADT agents, as you know, are given by urologists and they don't have internal medicine training, but they certainly have a lot of experience. What tools are available to help them to try and keep lipids and cognition and fracture at the forefront? Is there anything that pulls it all together or do you have to à la carte each one of those complications?

Charles Ryan: That's a great question. And I think that the short answer is that there isn't one place to go where you can get all of these things addressed. To take a step back, we urologists, oncologists, anybody who's addressing these patients, we really have a tremendous opportunity in many cases because patients may come to us and they may just not have good general health and they may get diagnosed with prostate cancer and they go on ADT, and they're thinking that the prostate cancer is by far this big existential health moment that they have. But in some cases, it's the first time that they've been cared for continuously by a physician for a long period of time. So the opportunity to identify and address some of these risk factors very early on can maybe lead to saving a life, not from prostate cancer, but saving a life from cardiovascular illness.

So I said the internal medicine part, not to say that we need to be board-certified internists to do this, but a lot of it comes right out of this sort of training and environment that we have. Lipid management, even early diabetes management, blood pressure management, is at this point, not complicated in many cases because the agents that we can use are very well tolerated, generically available in many cases, et cetera. So what I would suggest to any physician who's taking care of such patients is that they have a resource, an online resource like UpToDate and other ones that they can go to, that can help address changes. UroToday has many great resources on how to treat patients early on. And in particular, some of these online resources can give you doses and schedules of how to do things, and when to start a statin, for example, when to start a metformin, how to monitor patients, et cetera, et cetera. And as with all things in medicine, if it's something that gets a little bit out of your area of expertise, there are others who can do this. And so I really enjoy the conversations I have with the primary care doctors of my patients in these settings where we have this conversation like I point out, you may not know this, but the treatments that we use for prostate cancer may increase cardiovascular and metabolic risk.

Michael Cookson: Yeah. Another follow-up question I have for you on bone health. So it appears that there's good guidance for use of some of the bone-targeted agents for men who have bone disease, especially in the castration-resistant setting. But what I've noticed is sort of an underutilization of bone-strengthening agents in the non-metastatic setting. What guidance do you have for us on that?

Charles Ryan: Right. So that's a great observation and you're right, that men without bone metastases who have osteoporosis probably are undertreated, or those who are at risk for osteoporosis are probably undertreated, and there are a number of agents that are available ranging from the bisphosphonates that are used outside of the cancer setting, to the drugs that we know in the cancer setting, such as denosumab and zoledronic acid. They can be given at different doses and different schedules and they are typically in the non-cancer setting. Zoledronic acid can be given five milligrams once a year, and that can increase bone mineral density. And denosumab can also be given every six months with a similar effect subcutaneously in the office. And so those are available.

And I think that from a sort of a treatment perspective, one needs to ask, are we seeking to prevent the loss of bone or are we seeking to improve bone density? And so in a patient who comes in, who is at risk for bone loss, which is virtually anybody who goes on ADT, they should be doing the conservative measures, calcium, vitamin D. You should check their vitamin D level and they should be encouraged to do resistance exercise. For those who have already experienced bone loss, this is a situation where we may want to consider an agent to increase the bone mineral density. And Dr. Smith can comment on that too because he's done a lot of this pivotal work.

Michael Cookson: Matthew, would you like to comment on that?

Matthew Smith: Yeah. I think the overarching point is one that Chuck had raised in his presentation, and that is what you really need to assess an individual's risk for fracture. And the FRAX tool is a very good way of assessing that. Once you've used it a dozen times, you almost don't need to use it anymore because you can identify the risk factors that would drive someone to surpass a threshold for drug therapy. But it's really important. It's a very quick, easy tool. You can be done with or without measurement of bone mineral density. It's really our obligation to look at that for patients, certainly patients starting ADT. And I would just add as a useful comment that when you're using the FRAX tool, you should add secondary osteoporosis, check that box in any patient who's on ADT. And even then, it probably underestimates the true fracture risk.

Michael Cookson: Those are excellent points.

Alicia Morgans: So Dr. Ryan, did you have a question? I know, certainly, you touched on a lot of these points, but did you have any questions for Dr. Smith or vice versa as we're able to converse right now?

Charles Ryan: Well, I guess, the question that I would have is how aggressive do we need to get into pre-ADT cardiovascular screening? Should we be sending patients for stress tests? At what point do we want to be doing sort of next-level screening for patients at this day and age?

Matthew Smith: So it's a good point. And I'm reminded to make this comment again, which is that I think a lot of times, there are two camps, two extreme camps, maybe like our current political environment. There are those who say, "ADT doesn't cause any problems. It never causes cardiovascular problems." And then there are others who say, "It's responsible for every cardiovascular event that occurs." The truth is that neither is true. And most patients bring to their start of treatment most of their cardiovascular disease risk, and then ADT may modify that. But the data that's been published suggests that the effect, if real, is fairly modest. And when we looked at this in the Keating data, for example, you could kind of like attribute the increase in risk to the same as stopping a patient's statin.

So it's kind of that magnitude of effect. And the number needed to harm, depending on how you did the analysis, is quite large. You need to treat a lot of patients to cause one additional event. So we really need to look at the totality of a patient's risk. And most of that is going to be driven by other factors. So to your point though, I mean, we really need to consider that in a comprehensive way to help a patient have the best long-term outcome, to inform a decision about whether they should be treated with ADT or not. And there's a variety of settings where that comes up, right? The intermediate-risk prostate cancer patient whose getting radiation, your decision to add ADT or not, which is going to be an incremental benefit should consider their age and the rest of their health.

And then if you do decide that they should be on treatment, how much further can you improve their medical regimen to reduce the risk of future cardiovascular events? That's typically where I engage their internists and cardiologists. I was impressed, Chuck, that it sounds like you're quite willing to take a lot of that on in your own practice. But, what advice can you give to others, both medical oncologists and urologists, who aren't comfortable doing that? Meaning who aren't going to be doing a risk assessment for cardiovascular disease or prescribing statins or metformin. What advice do you have for those practice models?

Charles Ryan: I hope I didn't overstate my prowess in this area, but no, I mean, I will start an antihypertensive and I will start on a metformin, and typically I make sure that the primary care doctor if there was one involved and frequently there isn't, which is a challenge, I make sure that they're involved in the decision-making. Advice for others is again, how are you going to practice medicine is all about staying within your comfort zone and finding help when you need it. And there are some clinics, some big cancer centers that have survivorship clinics that take on this type of work and primary care doctors even embedded into the cancer centers. So, I think it's certainly reasonable to know how to manage early-stage hypertension with a diuretic and a calcium channel blocker.

These are not complicated drugs, and it takes you 10 minutes to think about them and read up on them and give them. Diabetes is a different question because, to be honest, somebody who's diagnosed with diabetes, deserves almost as much of a comprehensive workout as a person diagnosed with prostate cancer, right? Because there are kidneys to think about, and eyes and all kinds of other things. So I'm certainly not suggesting that we avoid endocrinologists and diabetologists in those cases.

I want to go back to one point, Matthew, that you brought up. One study that always stands out in my mind is the Canadian Intermittent Versus Continuous ADT Study for Radiation After Radiation Failure, published by Juanita Crook in the New England Journal of Medicine. And this was a negative study with regards to the intermittent hormonal therapy, suggesting that intermittent did not improve prostate cancer outcomes, mortality was the same.

But, when you look at the mortality in the continuous ADT group, that mortality was from cardiovascular disease, and when you look at the intermittent arm of that study, there was more mortality from prostate cancer. So I always looked at that study and I thought, well, that's evidence that what we should do, is we should probably improve our hormonal therapy. We should probably continue to be giving better and stronger ADT, while at the same time, trying to control the cardiovascular risk of our patients. And I wonder what your thoughts are on that study in particular.

Matthew Smith: It is an intriguing observation and it may be true, but it's worth noting that the cause of death analyses are really post-hoc. There was no careful confirmatory determination of the cause of death, that sort of thing. So it may be true. Ultimately, if there's the same number of deaths and they had to die of something, and there were no differences then you might see differences, but we do have to be really, really careful in overstating what those studies mean because the studies were never designed to ask those questions. But again, I stand by what I said, "It might be true." And I'm reminded of another way of thinking about this, I think was quite complimentary to yours, which is the consequence of intensifying therapy, both giving it earlier, and in some cases, giving multiple drugs, is to improve prostate cancer survival, but at the risk of greater non-cancer morbidity and potentially mortality.

And so it really is our increasing obligation to consider those things. And if we extend that to other common clinical settings, where we're giving additional systemic treatment for metastatic castration sensitive prostate cancer, and having better outcomes and extending that to patients with lower burden of metastases or in some cases, no detectable metastases, we really have to think carefully about what we're trying to accomplish and what the costs of better cancer control may be.

Alicia Morgans: Great. Matthew, I have a quick question for you about combination therapies because we use ADT in patients who are getting radiation, of course, but we also use it in long durations for patients with metastatic disease. And as we start layering on additional therapies for intensification, whether that's for the metastatic hormone-sensitive setting or the metastatic CRPC, non-metastatic CRPC, we know that the oral agents like abiraterone and enzalutamide tend to, at least in some post analyses, retrospective analyses, dataset analyses, seem to increase risk.

Interestingly, in some of those, it's actually just all-cause mortality, particularly in patients who have cardiovascular disease underlying their comorbid illnesses. But it also seems potentially to be driven by some cardiovascular risk. What is your thought on those particular patients? And a sort of follow-up on that is, if you had an agent and you do degarelix that could reduce risk, do you find that you use it more in those kinds of patients who are getting combination therapy, or would you perhaps in the future, should an oral agent be available?

Matthew Smith: Yeah, so I have not to date used degarelix for the purposes of greater cardiovascular safety. I think the most important attribute of GnRH antagonist is the ability to achieve more rapidly a castrate serum testosterone level. And that's important for the occasional patient whose at high risk for flare. So I think that's its far and away most important role in our current armamentarium. And then there may be this unexpected benefit of lower cardiovascular risk, but you do, you do point out all those settings that you described.

We have evidence for improved overall survival, at least in the patients studied in the trials, where we have to be careful is extending those observations to patients at lower risk of prostate cancer morbidity or mortality, and at greater risk for non-cancer morbidity or mortality, meaning older frailer patients with cardiovascular disease, meaning moving away from the patient populations that were studied in the trials. But even within the patients in the trials, we might even do better for overall survival, if we can reduce that non-cancer mortality which we may be unintentionally increasing to some degree by intensifying their systemic treatment. So I don't know if I answered your question or not, but I think I certainly agree with the principle that you've raised, which we really need to think about the totality of what we're doing.

Alicia Morgans: You definitely answered my question. And as always, I agree with you. And so just one quick final question for Dr. Ryan, as we wrap up. You do take on a lot, it seems, in coordinating things like blood pressure and taking care of the whole patient, which is great. And I don't always find that I have the bandwidth to do blood pressure control, think about lipids, and certainly diabetes control, as you mentioned. Do you have any words as we start to wrap up about how to best collaborate with folks like primary care and cardiologists or cardio-oncologists?

Charles Ryan: Well, I find this challenging being at an academic medical center where so many of my patients come from such different regions within our area. So it's not like I have one doctor that I send my patients to routinely. We do have a cardio-oncology clinic at our center. And I think all of you work at places that have similar things and that's actually an area that's going to blossom, I think over time, in particular, because of the factors that we're discussing. In many cases, they were started around the ideas of immunotherapies. But I think supporting those types of efforts in cancer centers, which they also have trainees in cardiology, going out into the community now, perhaps and practicing preventative cardiology. So, there's no single answer to that question, Alicia, you have to kind of know your place, your region, and what your resources are available.

Alicia Morgans: And you have to emphasize the need to really collaborate and to communicate, which I think as physicians, we all know at heart, but sometimes it takes a good reminder, thinking about the multidisciplinary care required to deal with the complications of androgen deprivation. And I will pass it back to Mike to wrap things up.

Michael Cookson: Yeah, thank you. This has been a great conversation and a great reminder to all of us, of some of the unintended consequences of our cancer therapies in men with advanced disease, a cautionary tale, and perhaps an opportunity for us to do better as we pay closer attention, particularly to the diabetic and cardiovascular and fracture-related complications. So I want to thank all of us. I want to thank Dr. Matthew Smith and Dr. Chuck Ryan. And then, of course, Alicia Morgans for this outstanding presentation, and look forward to more conversations on this topic.

Matthew Smith: Thank you.

Alicia Morgans: Thank you.