Michael Cookson: Thank you. I'm Dr. Michael Cookson, Professor, and Chair at the University of Oklahoma, and I lead our GU oncology group at the Stephenson Cancer Center. It's great to be here today, and that was a fantastic talk by Dr. Spratt, not only reviewing the historical perspectives of ADT and its use in radiation therapy but bringing it forward to some of the more contemporary antagonists that we think are coming down the road.

So, my first question is really one about the duration. I like your simplification of that low risk, intermediate, and high, but now we have the grade groups, and we have grade group 3 and grade group 2 patients that are both probably involved in those old intermediate. How do you prescribe the duration of ADT in those grade group 2 and 3 patients using what you know now?

Daniel Spratt: Intermediate-risk prostate cancer, some say it's the most heterogeneous type of localized prostate cancer because it goes from patients that are grade group 2, that potentially are eligible for active surveillance all the way to patients with grade group 3 with PSA of 19 and almost the entire prostate that effectively behave like high-risk disease. So, I think the first step I would say in simple terms is the NCCN subdivides intermediate risks into something called favorable and unfavorable intermediate-risk prostate cancer, a system developed out of Sloan Kettering. And we recently just published a post-hoc analysis but randomized trial validating that. So it's the first trial that's really validated that men with favorable intermediate-risk disease, which is primarily those grade group 2s, do not appear to drive benefit from hormone therapy. Whereas the grade group 3s are these unfavorable intermediate risks appear to have a survival benefit adding hormone therapy.

Regarding duration, it's somewhere between four to six months. Some people will say it should be foursome will say it to be six. There's not amazing data what it should be. One of the big areas, what we don't know is now that we're giving more and more hypofractionated radiation, where we're not giving eight, nine weeks, we're giving sometimes as short as five treatments, it's really unclear what that optimal duration should be. And so that's where I'm excited for some of these new forms of hormone therapy because it allows like I was saying, that fast on and off. And so maybe it's three months you need, maybe you need 12 months. No one really knows, but it's definitely something that's probably at least with our traditional hormone therapy in the four to six-month range.

Michael Cookson: Thank you. Another thought I had when you were presenting that, and I appreciate we're all becoming increasingly aware of the cardiac and the bone deprivation and even the cognitive components of side effects with these therapies. As you look at what you know to be the data, for example, for high-risk patients and you introduce these new oral antagonists that have an on-off switch that get them back up, do you think we'll have to rethink the duration of therapy because as you pointed out, we got a lot more bang for our buck? We might've intended 18 months, but we got three years. Do you think that'll alter our approach to how long we will need to apply the hormonal therapy?

Daniel Spratt: Absolutely. I almost feel there are two different areas that I hope get investigated. One of which there are trials that are ongoing some of the completed about adding next-generation forms of hormone therapy on top of things like leuprolide, that's just enzalutamide, apalutamide, and abiraterone. And some trials seem to launch what many people and there are some trials we've participated in that are Phase II trials is they've shortened that duration to like six months for high risk, but they've intensified the intensity of hormone therapy with these newer forms of hormone therapy, trying to say, we're going to give it all, but in a condensed period, find it truly cure to them. And the alternative, as you said, is if we replaced leuprolide with something like, let's say relugolix, the on and off switch. I'm not exactly sure what that optimal duration should be because as I said three to six years that are being castrated with leuprolide. So I think those studies would be great to conduct to better personalize it for patients.

Michael Cookson: Thank you.

Alicia Morgans: Great. I think that's actually a huge question and I look forward to you and the group at NRG and in other settings really flushing that out because I do think there are still questions there, but I think in terms of tolerance and in terms of cardiovascular risks, this is really enticing to me, certainly as a medical oncologist. And I think to you too, as you think about competing risks, I'm just curious, do you think that really those patients in the HERO trial who over 90% seem to have had at least one risk factor for cardiovascular disease, do you think that that population represents the men that you treat every day? Honestly, I think it represents the men I treat or perhaps even a little healthier version of the men that I treat, so I'm just curious from a radiation oncologist perspective, what your thoughts are.

Daniel Spratt: It's two things. One is they did a subset analysis of the cardiac data from that HERO trial and did show that patients with a prior MACE event, a major cardiac event, benefited or had a substantial reduction in the development of another MACE event with using relugolix versus leuprolide. In those that did not have any prior history of heart disease or these cardiac events, it was numerically superior for relugolix pretty significantly. So basically saying that those with prior probable risk factors, it would benefit them the most.

The second is patients getting ready to use and the median age is about 68, 70 years old. I mean, that probably in and of itself is a risk factor for men with heart disease. But it is, I would say it's uncommon to find a 70-year-old with no history of high blood pressure hyperlipidemia, early or diagnose diabetes, et cetera. So I think it's very common to have at least one of these risk factors, if not multiple. So I would say that the results I think are very applicable. And as you said, depending on where you live in the US and the age of the patients, I think many men have actually more risk factors than that.

Michael Cookson: Dan, as urologists, we have not done a great job of assessing the cardiac risks of our men before we placed them on these therapies. Now, I think we'll be getting a little better at it. When you see a high-risk patient and you're scheduling out that 18 months duration, do you feel there could be a need to modify that based on the cardiac risk factors as to how long you would treat them balancing the cancer cardiac risk?

Daniel Spratt: Yeah, no questions. I think having a multidisciplinary team is very helpful, whether that's in collaboration with medical oncologists if you're able to, but also usually those cardiologists abundance, a cardiologist to discuss with them. And we do that not infrequently for patients who have heart disease to really understand the severity of their heart disease.

But I typically will say it is that balance as Dr. Morgan said about competing risks versus the benefit in cancer. And if I think long-term hormones, let's say 18 months versus six months, will provide them an absolute benefit of a few percent, I really need to weigh that against how bad their current heart disease is. And if I think it's going to be a few percent or more worse than their other cause mortality is serious decision-making, but it's something that we need to discuss. And I have actually had patients who will happily say, "Protect my heart, I want very minimal hormones. I understand I'm at higher risk of recurrence of my disease." And I've had some patients say, "Give me all the hormone therapies, I'd rather die of heart disease than cancer." And so I think it's just being open and transparent about what we know and what we don't know.

Alicia Morgans: I think that's great. And I just think to take that a step farther, how do you talk about cardiovascular risk with your patients? Because I think part of our purpose in all of this is to give urologists, medical oncologists, radiation, oncologists, and other clinicians practicing providers, a roadmap for how to address these issues because we've known that they've been there, but sometimes in the midst of taking care of cancer, we don't really emphasize these pieces just because there's so much going on, but we do need to emphasize them. We need to explain them. How do you do that in your practice?

Daniel Spratt: Step 1 is I think just making sure you understand where they're at today. And so that's an assessment of all potential risk factors within overall already, if they already have a diagnosis, whether it's they've had a stent if they've had a surgery for heart disease, if CHF, arrhythmia, I think it's really understanding because I'm not a cardiologist. Some of these I'll think that this could be troublesome and to the cardiologist, it's not at all. Their field has advanced tremendously. I just had a patient, he had a cardiac transplant a decade ago and he's probably in better shape than I am. And so I think sometimes we don't want to preconceive, we know what these conditions mean. But second is I go over the data that's available with them and it's related to cognition falls, development of heart disease.

And what's interesting is I think with the hormone therapy, and I'd be curious either of your perspectives is it seems to be actually many of the arrhythmias seem to be more predominant in terms of, and or heart failure than actually when we think of ischemic heart disease because I think a lot of times the studies when they only look at ischemic disease, it's variable, the association. But I think sometimes it's these arrhythmias that we never have tied to the therapy that can lead to heart disease over time. And so again, I think they're just trying to be openly transparent with them.

Michael Cookson: And I think as these newer agents come available and we've talked about this in some other formats, looking at those drug-drug interactions, and if we are increasing the risk of some of these things that are unintended consequences and the important role of cardio-oncology going forward in our multidisciplinary model.

Alicia Morgans: I completely agree. As we think about this and we want to put it all in context in terms of radiation oncology, and certainly, in terms of treating prostate cancer overall, Dr. Spratt, what would your overarching message be from a radiation oncologist regarding cardiovascular health and the use of androgen deprivation therapy in that setting?

Daniel Spratt: I think any time that I'm going to prescribe hormone therapy with radiation I tell patients, number 1, if this was not going to benefit you, I would not offer to chemically castrate you. So there is robust data to the potential benefits of it. Number 2, that actually probably the best thing that they can do to lower the risk of almost all of the side effects of hormone therapy, especially when we're talking about finite durations is physical activity and a heart-healthy diet. And I really can't emphasize that enough. And the guys who I tell them, they need an extra 10 minutes of vigorous activity a day. If I'm going to give them hormone therapy, it's like two prescriptions that I'm handing you, one for exercise, one for hormone therapy. And guys who do it, I mean, almost none of them will gain body fat. They usually maintain, but I say, you have to do this 10 minutes exercise for a day. But if you're someone that's now been diagnosed with prostate cancer and you've been recommended radiation and hormone therapy, I think it's important for you to discuss with them your concerns about it. If you have prior risk factors for heart disease, a family history of it, and maybe see a medical oncologist and maybe see a cardiologist. I think these are all reasonable things to do if you have a lot of concerns.

Alicia Morgans: Thank you. And Dr. Cookson, what would your thought be?

Michael Cookson: Well, I think that his points have been excellent. We're looking at a more tailored approach to the added value of the androgen deprivation therapy in patients that are undergoing treatment for advanced disease, as well as treatment for localized disease and locally advanced. I think that shorter duration of therapy is likely to benefit them as long as it's effective. And just like we're compressing the radiation into a shorter timeframe with the hyperfractionation. I think these new agents will allow us to be able to reduce the lingering long-term side effects of ADT, which are really bothersome to these patients, especially those with the ability to come off therapy. I think it's great.

Alicia Morgans: I agree. And I think as we all think about this, ultimately, the purpose of treatment with radiation and hormonal therapy is to cure men. And if we are able to do that in a way that allows them to have faster recovery of testosterone, but maintain that cancer control simultaneously, I think we've really hit upon a winner. So this is really what we ultimately aim to do: improve lives, lengthen lives and improve quality of life. And so whatever way we can do that in terms of maintaining and maximizing cardiovascular health too, is always important. Thank you both for your time today. Thank you for your expertise.

Daniel Spratt: Thanks so much.

Michael Cookson: Thank you.