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Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira here at the Prostate Cancer Foundation. Joining me today is Dr. Dong-Woo Kang at Dana-Farber Cancer Institute. He will share his recent study, "Effects of High-Intensity Interval Training on Cardiometabolic Biomarkers in Patients with Prostate Cancer Undergoing Active Surveillance: A Randomized Controlled Trial." This was published in Prostate Cancer and Prostatic Diseases. Dr. Kang, thank you so much for joining us today.

Dong-Woo Kang: Thank you so much for the kind introduction, and I am very excited that I've been invited, and I'm really thankful so that I can share some of the findings we found recently. I think we have quite limited time today, but I'll be nice and efficient. I'd like to highlight some of the potential roles we found from our recent ERASE randomized controlled trial, that what exercise could offer, particularly for patients undergoing active surveillance in the prostate cancer settings. Just a reminder that I'm at Dana-Farber and Harvard Medical School as an instructor, but I'll be moving to the Fred Hutchinson Cancer Center as assistant professor starting next year. If there's anything—you have any questions—I might not be here anymore after this year, but you can reach out to me through other email addresses I might give you later.

And then I'll just really briefly touch on what's going on with the patient because I want to highlight this study from Dr. Loeb et al., in 2017, that a lot of patients are confused during the active surveillance period per se, as they don't know what to do to manage their health mostly. As an exercise physiologist and an exercise scientist, I do know there's very strong evidence about the benefits of physical activity for general populations and overall cancer populations, and also particularly for prostate cancer patients. But there's no clear guidance for the patients and also particular studies that are showing more medical or clinical benefits from the physical activity or exercise. And patients are getting together trying to get that information as much as they can, so our work is trying to address or help their journey during the active surveillance, at least the exercise science and what we can offer for the patient.

And in that active surveillance setting, we know that it's very unique more recently that they are just being monitored and not given any treatments, and they want to improve or keep good health during this period. And then what I thought could be possible is, especially they're having their prostate tumor in place, and then if exercise is given—and there's a lot of things going on physiologically as an exercise science—some of those can be immune function, and there's some metabolic markers and some inflammation markers that can help in a positive way that they can eventually or maybe reduce cancer progression and reduce comorbidities, and they can help patients remain on active surveillance and potentially improve their survival and the quality of life as well, mentally and physically. This is the promise that I was seeing before we conducted the study. We have approached approximately 52—or recruited 52—patients, and then they are randomized to either exercise group and the control group, and then they're given 12 weeks of exercise or not.

And then they were assessed. And then this particular exercise program was a supervised aerobic high-intensity interval training. It's a high-intensity aerobic training that's done multiple times throughout the session with a shorter period of high intensity and then recovery, and repeating multiple times. And they did it for 12 weeks, three times a week, and then they did it on a treadmill, and we measured many markers. And one of our primary interests was prostate cancer tumor markers as the PSA and then relevant markers, and then other cardiovascular fitness and then health- or disease-related biomarkers. And I'm not going to go through everything today, but I'm going to highlight some key findings that we were very excited about. This finding was published in 2021 in JAMA Oncology, that we found that exercise group, which is in this blue color, had a lower—slightly lower—PSA level after the intervention.

And compared to usual care group, it was significantly different, and there was within 12 weeks, and we saw 1.1 microgram per liter, which is pretty interesting. And after also we are looking at the cell line within the systematic blood cells. Then we looked at this LNCaP, which is androgen-dependent prostate cancer cell line growth. And then exercise group had, in general, the lower cancer cell growth compared to the usual care group, which was 5% differences, statistically significant.

And in this recent publication, what we found, which is also exciting, was these are testing insulin markers, and then IGF, which is insulin-like growth factor. And there's another binding protein, which is also another marker, that altogether we can interpret it as metabolic markers, or they are highly associated with metabolic disease including diabetes and then metabolic syndrome and hyperlipidemia. When we look at this, insulin level was decreased in the exercise group in this blue compared to this control group orange dots.

And then IGF-1 is also another marker that—the higher level is a poor association with the metabolic outcomes—and then it's also improved. And IGF-BP is a good marker that exercise had an improvement after 12 weeks, and then usual care group had a decline in this marker. We have other findings that we didn't present today, but there's some other immune markers and inflammatory markers that we found that's also relevant to other diseases and also some lipid markers improvement for cardiovascular. But for this study for today, I will not just highlight that exercise, particularly this program, high-intensity exercise program for 12 weeks, significantly inhibited biochemical progression of prostate cancer. And then some of the biomarkers associated with metabolic diseases were also reduced after this particular exercise program.

We want to interpret this with a little bit of caution because this is a smaller study relatively. We have 52 patients, and this is a very particular exercise program. We were not extremely excited that everybody should do that exercise, this high-intensity training. But this study is a phase two—we call it a study is a little smaller—but we have to interpret it: there might be some benefits on these tumor markers and about metabolic health conditions for these patients. And then we will need to do some further investigations in larger clinical trials, recruiting hundreds of patients, especially we want to look at—or I am actually developing some—the larger phase two trials to look at their actual survival or the long-term follow-up analysis in terms of their cancer progression, metastasis, as well as their comorbidities. And again, the patients on active surveillance are concerned about their health in general because the risk is relatively lower.

And then the number one cause of death for prostate cancer on surveillance is actually cardiovascular diseases, which is three times higher than the prostate cancer itself, which is also giving us a sense that patients probably want to take care of their health in general, not just for the prostate cancer. I would like to say that physicians and patients can start incorporating physical activity in general, as the guideline says. If you want to do some more structured exercise, then patients are encouraged to consult with the exercise physiologist nearby, and then you have to be assessed for your health conditions at the moment and the goals, especially—everybody has—every patient has different interests and their basal conditions, and then we have to make sure that these exercises can be done safely and then for the purpose of their own goal. These are a quick summary of our recent findings, and thank you so much. And I'll take any questions you have.

Andrea Miyahira: Thank you so much, Dr. Kang, for sharing this. I noted that body weight was not improved for the 12 weeks of exercise. Why do you think this is?

Dong-Woo Kang: Of course, in most exercise settings, exercise is a way of—when you're thinking about the energy expenditure, exercise itself, easily put, is not a main modality to lose weight or body weight, that we are not even anticipating that patients will be losing weight after the exercise interventions a lot. If we are considering or we are targeting to lose their weight, then we will definitely want to incorporate some diet components. In a very, very rough put, then I would usually say that 60 to 70% or 68% are due to diet when we are targeting weight, body weight.

But exercise has a smaller portion contributing to weight loss. For this study, we were also not hypothesizing that they're going to lose weight. It's possible, but this is more for the physiological changes within the body during the exercise and then with the training. And then if we are not really controlling the diet, then it's very challenging to see the weight. And the positive side of this exercise is if they are in good shape or they don't have to lose weight, exercise still provides these findings, these benefits without controlling their weight—it's independent benefits from their body or obesity status.

Andrea Miyahira: Thank you. With this study and other studies, do you think that certain types of exercise are more beneficial, or if certain populations of patients are more likely to benefit from, I guess, certain types of exercise?

Dong-Woo Kang: I think this is a really, really good question, and it is a million-dollar question. We know there is a growing body of evidence that the high-intensity exercise seems to be more beneficial, and there's dose-response in terms of intensity and exercise. When you're thinking about a drug and there's doses that you're given more often or there's a high dose, exercise is a little more complicated because of your behavior, and exercise can have intensity—you can do running or walking—but you can do also 30 minutes versus one hour. There's also duration, then the frequencies, and then the total period of given. There's lots of things considering in terms of targeting a specific outcome. We have to consider those all together. And also we are just talking about patients on active surveillance, but if we can just step back and see the whole prostate cancer community, a lot of patients on ADT are receiving or experiencing the loss of muscle mass during the treatment and then increasing obesity rates.

And if we are saying that, "Which exercise is the best?" And it depends on what they're going through right now. For ADT patients, we are definitely encouraging them to do some resistance exercise together, not only this type of high-intensity exercise, because muscle loss is very, very common. But it also depends on their conditions with what they're doing. And in their time, if they have limited time to do exercise—for active surveillance patients, they are having a high risk of cardiovascular disease, and something that you can improve your heart conditions can help prevent from having or developing cardiovascular disease. I would then consult, depending on their conditions—if you have only 30 minutes a day, you could do more cardiovascular. But in general, rule of thumb, both exercises have both benefits in body composition and then cardiovascular side. You can take that as a more general idea. But definitely I would encourage everybody to consult with an exercise specialist.

Andrea Miyahira: Thank you. What do you think needs to be done to get payers willing to pay for exercise classes or equipment as a part of treatment?

Dong-Woo Kang: That's what all exercise oncologists are striving for, and it's not easy. An exercise physiologist is not insured within the medical care right now. Physiotherapy is, but patients will need to consult an exercise scientist that can provide a more structured and more specific exercise guidelines, meaning that we are including the study sizes of findings we just presented. What I think is important to persuade the doctors and then stakeholders is some of those clinical outcomes that are more—or clinical outcomes like cancer progression and comorbidities and then survival. And those are the important outcomes I am also looking at in a long-term follow-up for these patients, and we are generating those more profound evidence that can persuade those people that exercise is actually very important, and it's not just for their health source, the quality of life, and there's lots of components where exercise is beneficial for the patients. I think it is such an important avenue we are exploring. And then we need a lot of support from the medical doctors and the patient groups and then both researchers—we have to work all together.

Andrea Miyahira: Thank you. And what are your next steps in these studies?

Dong-Woo Kang: In fact, this is more like a foundational study that I am using as a preliminary study that I am expanding in a larger study at the moment, developing phase three clinical trial, likely in a multicenter trial, that we are trying to provide more like a virtual where it can be delivered to many patients. We are trying to recruit hundreds of patients on active surveillance with the long-term follow-up to see if there's any benefits on actual clinical events, meaning cancer progression or tumor progression, as well as comorbidities in their clinical events on the longer-term period.

Andrea Miyahira: Thank you so much for sharing this with us and for doing these really important and also difficult studies. Congratulations.

Dong-Woo Kang: Thank you very much, Andrea.