Noel Clarke: We come now to one of the topics, which is somewhat under studied and is really quite important. And Heather Cheng is going to take us through the data relating to the effects on muscle strength of some of the treatments, particularly androgenic treatments that we use in prostate cancer. And I think you'll find it quite illuminating. Heather.

Heather Cheng: Thank you so much. Good morning, everyone and such a pleasure to be here in person and for those of you who are joining virtually, and I really want to thank again, Silke and Aurelius and the Lugano team for their wonderful hospitality and it's great meeting. So I'm going to talk about how to care for muscle strength. Here are my disclosures. The top aren't so relevant. The more important one is I'm not an exercise physiologist and I'm not a body builder like Arnold Schwarzenegger. But although I'm a concerned clinician. So with that, these are the things I'm going to cover in the next few minutes.

I'm going to talk about some of the data on impact of muscle strength from ADT, with a focus on advanced disease treatments. There are some really nice historic data in the localized setting that I won't have time to cover. I'm going to highlight Foundational recent data and then some ongoing clinical trials that are really exciting. And then I'm going to talk about how I treat my patients and then end with some take home points.

So this, I think Dr. Saad mentioned is kind of how I think about prostate cancer disease states and at the bottom is the role for androgen deprivation therapy and really the point here is that's extending. We're finding these agents, AR targeting is being used earlier. It's more effective. Men are living longer. So we really need to be thinking about the adverse effects. So sarcopenia is associated with androgen deprivation therapy. Sar comes from the Greek term for flesh and penia for loss. And this was a term coined in the late 1980s to describe an age related phenomena of muscle loss.

But we also know that suppressing testosterone also can lead to reversal or to loss of muscle and gain of fat. Loss of muscle and increased subcutaneous and visceral abdominal fat is well recognized as a side effect of ADT. I'll show you some additional data in a moment. And loss of muscle strength increases frailty, which Dr. Morgans talked about, and worsens physical function and increases fall risk and disability. So we really want to be attentive to this.

And this is a study from Matthew Smith and colleagues from, now, 10 years ago, showing that ADT has lasting consequences. And this is looking at changes to lean body mass measured by total body DEXA at baseline 12, 24 and 36 months on ADT. The prospective study, about 250 stratified by age and duration of ADT. And the findings were really kind of what we might expect that lean body mass just decreases significantly at 12 months, 24 and 36 months. And also if people have been on ADT six months prior. This is more pronounced in our older patients. So definitely something we need to be thinking about.

And then as a medical oncologist, we talk about short course. Short course is actually not so short for patients who might be on treatment and experiencing side effects. This is the visualization of a paper from 2021, showing that on the left baseline in red is the skeletal muscle and that decreases after six months on the panel on the right. And then blue is the subcutaneous fat, which increases. And then in yellow is the visceral fat. So just visually you can see that there's a difference even after six months.

So if we see these changes with six months of ADT, then you can only imagine what the impact of a longer duration and a more profound AR suppression might be. So here's some work from, I think Johann de Bono and group after the abiraterone study. And this is looking at muscle analysis using CT based imaging of [inaudible] and showing that there are changes in muscle before and after starting ADT shown on the right panel. And so with abiraterone and dexamethasone, you can see a pretty profound change in muscle. And this is, I would point out patients who had been in the metastatic castration resistance setting. So they had already experienced some changes from ADT and now were adding on an additional agent. This is some more recent data from Dr. Gillessen and colleagues looking at the effect of abiraterone and enzalutamide on body composition in patients with mCRPC.

And in this study, there were 54 patients treated with abi or enza at a single institution and the changes were measured by CT scans after meeting of about 11 months. And there was a significant loss of skeletal muscle versus baseline observed for enzalutamide and while on the abiraterone. And this was not powered to compare the two with each other but we know that there are detrimental effects.

What are some of the mechanisms of action? I just want to highlight a colleague from the VA, Dr. Garcia, who's looking at mitochondrial dysfunction as the possible explanation or mechanism of action. And so there are studies on going to try to understand the physiology of ADT and potentially treatment outcomes. But maybe what we were interested in knowing is could there be a pill to make exercise obsolete and what if there would be such a thing and wouldn't that be just splendid?

Unfortunately, I would say nature is more elegant than our research and development. And so on the panel on the left is a few years old now, trends in pharmacologic sciences of different potential avenues of looking at exercise pill. I'll just tell you we're not prime time yet. And so looking on the right is combined resistance in aerobic exercise. We know that this reverses muscle loss in men undergoing ADT. In this study, it's early disease. So patients that do not have bone metastases, and this was a randomized controlled trial from 2010. [inaudible]. And there was no picture from that so I borrowed a picture from the weight loss study. But basically showing that combined aerobic and resistance exercise is effective and can reverse muscle loss, that's the point.

What are some of the potential mechanistic effects of resistance training? So I won't go through all the details, but some of the mechanism adipokines, and myokines, epigenetic effects, oxidative stress, psychological wellbeing. I would point that out, it's really important for our patients. Chronic inflammation and metabolic effects. So these are all things I think will, as we move forward, be important to be looking at and understanding.

So here's some recent data resistance in aerobic exercise. I would say combined resistance and aerobic exercise helps reverse muscle loss in patients who are on ADT. And the first study was one with patients who had been on ADT for over two months. And it was a combination for 12 weeks or usual care and showed that there was benefit. Second point is start early and offer support. So in another study, patients who had not yet started ADT, but were planned for ADT were assigned three months of supervised aerobic activity followed by three months of self-directed exercise. And there was benefit at three months. And then patients note these benefits. So in the third, there was a smaller study, 25 patients assigned a 12 months of home-based progressive training at the start of ADT and they noted improvements in general wellbeing health, mental health, as well as vitality. So this is something patients will notice that's an improvement in their quality of life in addition to all of the other health benefits that we talked about.

So this brings me to advanced disease study, which I think is really exciting. INTERVAL-GAP4. We have it at our institution. It's a randomized control phase three study for patients with metastatic castration resistant prostate cancer. If you're wondering about this later, it's on page 21 in your program handout. And the question is, could intense exercise beat advanced prostate cancer? And the primary objective of this really nice study is to determine if high intensity aerobic and resistance exercise using a supervised approach three hours with a trainer per week, plus psychological support increases overall survival compared to psychosocial support alone. And so I think there's a lot of other secondary objectives that are really exciting and there's going to be nearly 900 patients in international study. So I would encourage you to check out the study to encourage your patients to enroll. Because I think this is going to be really important for the field.

This next slide, I won't go into detail, but you can take a picture of it and refer to the top row of, I think, really intriguing studies and important studies. The top row is INTERVAL-GAP4 study that I just mentioned. And then there's a study called GET FIT, the Knight Cancer Institute at Oregon Health Sciences that also includes three arms with tai ji strength training or stretching control, which I thought was really cool. And then Dana Farber had the study of Exercise to Enhance Cardiovascular Health Among our Black Patients on ADT. Also, I think really important. And then Belfast has a really interesting study Exercise for Advanced Prostate Cancer: Multi-component Feasibility Trials. So there's some really exciting trials available. And so I would encourage you to seek these out and encourage them for your patients.

Not everyone has access to those. And so what can you do for your patients otherwise? So we actually at the University of Washington and Fred Hutch have videos on tailored exercises for prostate cancer patients. And there's some videos that are available for everyone. So if you want to, you may have some you want to direct your patients to these videos. I think they're really nice. They can do them at home with very little equipment.

So how do I treat my patients in this situation? The first thing I do is ask them what they do and you meet them where they are. So I think our patient, Mr. Matheson was talking about this. Share the data. Data I just mentioned. Discuss the physical, the quality of life and the survival benefit. I invite goal setting. So can you do 20% more? How would you measure it? And you ask that of your patient. If they already do stuff, that's great. You have such a strong cardio practice. Can you incorporate resistance into your practice? Social exercise has better uptake and follow through. And so referring to a clinical trial, referring to a physical therapist, referring to the support group, video education that I just mentioned, ask and ask again. Encourage, celebrate and reinforce.

On the right side as the stages of change. So this is actually from weight loss and like quitting smoking, but it also applies to adoption of new, healthy habits. So, no, not me. Well, maybe. The third is, okay, what do I do now? And then that might be a teachable moment. Okay, let's do this. And then it's possible you maintain it, that exercise program. So these are things I think are important and things we don't necessarily think about when we're in the mind frame of prescribing medications.

So here are my summary and take home points. ADT can lead to sarcopenia, even after a short course. Negative effects are further compounded with deeper AR suppressions, which is abi, enza, daro, so forth. Exercise, especially aerobic and resistance can mitigate negative impacts. Lifestyle changes require different approaches in prescribing medication, but can have comparable, if not, arguably more impact and positive effects on patients' wellbeing. Medical approaches are certainly being studied, but please don't wait for these. Be your patient's advocate and sponsor. Meet them where they are, motivate them, avail them of clinical trials and support. Physical therapy, caregivers and support groups. And just to echo what Dr. Saad was saying with earlier use of next generation AR blockade and longer overall survival, we really need to be thinking about survivorship with advanced prostate cancer. Because our job is to improve the quality of life, not just to delay death. And so hopefully all of our patients can have exercise and fitness well enough to hike to the top of, [inaudible], and feel like that little stick figure up there. So thank you for your attention.