Charles Ryan: Thank you to the organizers and to all of you for showing up to pay attention to a talk on fatigue and cognition in prostate cancer.

I have noticed a significant trend here of people showing the cities from which they come, which I think is great. This is Minneapolis, known to the United States as the City of Lakes, and you'll see a few of these lakes during my talk. These are my disclosures. This is Lake Harriet. I live along the shore of this beautiful lake.

Life while androgen deprived is not a breeze. Fatigue is very common. Approximately 40% will complain of fatigue levels that will interfere with activities of daily living. We are now moving into an era where we're not simply doing ADT, and we've had many sessions which have talked about layering in additional therapies whether it be potent AR targeted therapies, chemotherapies, et cetera.

Long term, there is a concern that is arising in the literature, I'm sure you're seeing it in your clinics, about an association with dementia or a permanent cognitive decline. We don't know much about the biological link of this, but we can explore some of the data that do exist.

I point out that in APCCC 2017, fatigue and cognition were, for us, as a body of consensus makers, a key driver in therapy choice for mCRPC. Look at the dichotomy between choosing abiraterone or enzalutamide in patients who present with significant baseline fatigue or significant baseline neurocognitive impairment. We knew back then, and we continue to study this effect, that penetration into the CNS from an AR targeted therapy may make worse preexisting cognitive declines, preexisting fatigue, and similar situations.

I bring up two recent Phase III studies that were presented. This is the ENZAMET study and the ARAMIS study, to simply point out that when we look at adverse event tables in our Phase III trials, fatigue is usually the number one listed side effect. Now, fortunately, we don't very often see Grade 4 or Grade 5 fatigue, but we do see, very commonly, Grade 2 fatigue. In the enzalutamide arm, for example, of ENZAMET, we saw over 30% of patients, who experienced Grade 2 or Grade 3 fatigue. In the darolutamide study, albeit a slightly different patient population, we see 12.5%. So this is one in eight patients who are experiencing fatigue due to therapy that is interfering with their activities of daily living.

So, I think you knew this, but I'll just put some numbers around it. This is a common problem and perhaps we're moving through our clinic days relatively quickly focusing on PSAs and scans and things like this and fatigue is something we probably don't spend enough time talking about because, let's be honest, we don't really have great answers for this issue.

I also think that fatigue is an interesting biomarker in a way. Fatigue is both a factor related to the treatment, and we shouldn't think that fatigue is only due to androgen deprivation therapy or due to targeting the androgen receptor. Fatigue is actually a disease factor.

This is a great chart that I like to show from the LATITUDE study presented by Kim Chi at ASCO a couple of years ago. What they showed was in patients on the abiraterone arm from the LATITUDE study, fatigue actually got better. So lest we think our therapies are simply going to all make fatigue worse, if a patient's clinical status is overall improving, you are likely to see a concomitant reduction in fatigue. I think that's an important thing to keep in mind. Nothing is better than a successful therapy for a patient and even when that happens, they may overlook things like fatigue due to therapy.

But let's take a step back and let's ask what is fatigue? Fatigue is probably a lot of different things, you know? When we think about targeting the androgen receptor penetrants up to the CNS of our therapies, and we think about the short duration of time we actually spend with patients talking about these symptoms, people may essentially roll up a whole series of other underlying clinical events into fatigue.

And the two that I think of most commonly are cognitive decline, I think people who are experiencing a subclinical cognitive decline may simply describe to you or you may perceive fatigue, and depression. And these are two very common events in the aging male. And I put next to this iceberg idea, the facet fatigue scale. And what I would like to encourage is that all of us who are doing clinical trials where we're manipulating the androgen axis and giving therapies that may cause fatigue, let's not simply report fatigue as we did when the ARAMIS and in ENZAMET studies, using the CTC criteria. Let's begin to get a little bit more granular about some of these patient-reported outcomes in fatigue and let's use the validated instruments that the field has provided for us so that we can get a little bit of a better view on what fatigue actually is.

Again, I'm going to cite some data from Kim Chi who has done a lot of great work on this. But this is with an enzalutamide versus abiraterone randomized trial that's been presented and what they used is the PHQ9 analysis and the MoCa analysis. Now, neither one of these are perfect instruments for the measurement of depressive symptoms or cognitive impairment, but they seem to suggest in his study that there was an uptick in depressive symptoms in the enzalutamide group after about 12 weeks of therapy. Using the MoCa analysis, which is a relatively insensitive test for cognitive change, they showed no significant difference between abiraterone and enzalutamide in patients after 12 weeks of therapy, although there was an uptick again in the overall incidence of some of these cognitive impairments. What we don't know of course is where were these patients to begin with in terms of their risk? And we don't really quite understand the biology of the cognition here.

But I'm now going to present a hashtag that I hope catches on, which is, #BenchpresstoBedside. We need to be doing some bench press to bedside research, and here's a really nice example of why. This is a study from Australia, a randomized trial of exercise interventions versus support only followed by deferred exercise interventions in patients experiencing fatigue from cancer. And what they showed is that those who began the study with the highest quartile of fatigue, the most fatigued patients. Had the greatest reduction in fatigue from the exercise intervention that was given to them. Vitality as is defined here on the bottom of the slide also improved substantially. So your patients who've lost the most have the most to gain from exercise. And that's one of the key points that I think we want to get across as we think about mitigating fatigue.

Keep this in mind for you Star Trek fans out there, when it comes to exercise resistance is utile. And that's because resistance exercise is actually better than aerobic exercise in not only reducing fatigue, it actually leads to obviously improvements in muscle strength, coordination, reduction in the risk of falls, et cetera, et cetera.

So the ILRT arm here is impact loading and resistance training and this is a measurement of the combined muscle strength equaling the sum of the chest press and leg press exercises. And look at this box, patients at baseline after 12 months of this randomized exercise program, their overall strength improved about 30%. That's pretty significant. And when you think that the therapies that we're giving are causing reductions in muscle mass, that's quite a feat. And so something we need to be thinking about as we progress in our #BenchpresstoBedside research.

I did an analysis of the literature on cancer-related fatigue in general and there's really not much of a conclusion beyond exercise, I will point out. Cancer-related fatigue is best managed by exercise and support not drugs. I in my own practice have from time to time tried methylphenidate for example. It has transient beneficial effects but no real longterm effects.

So we in our #BenchpresstoBedside program at the university of Minnesota are looking at weightlifting resistance exercise, not only in prostate cancer but, for example, in the recovery of the lost muscle mass that occurs during bone marrow transplantation. And this is one of my colleagues on our faculty who last week or two weeks ago became the USPA, US Power Lifters Association, national squat record holder while holding down a full-time job as a bone marrow transplant doctor and raising two children.

So the next piece of #BenchpresstoBedside is whether or not exercise may actually benefit overall survival. The GAP4 study led by Fred Saad was recently mentioned and that picks up on this epidemiological data showing that patients who exercise vigorously numerous times per week after the diagnosis of prostate cancer actually appeared to have a reduction in the risk of disease-specific death. So we may be doing something when we're treating that fatigue with resistance exercise.

Going to pivot to cognition now and how is it that androgen deprivation therapy can affect cognition? This is something that I've thought a lot about as a medical oncologist over the last few years. And there's actually a lot of really supportive and interesting data that tell part of the story but not the complete story. First of all, when you think about the role of the androgen receptor and its expression in the human body and our evolution as a species, probably the most important organ for which the androgen receptor should be expressed is in the brain.

And that actually is the case. The brain is replete with androgen receptors and in fact androgens functioning through the antigen receptor in the central nervous system are neuroprotective and a decline in androgens has been shown to lead to, for example, augmentation or associations with increases in beta-amyloid expression in the brain.

Now for non prostate cancer patients, androgens decline substantially after the age of about 70. So these curves on number three here are from autopsy specimens where brains were removed and androgens were assayed in the brain as a function of age. And you can see that these go down substantially.

So when we decline the androgens, what happens? Well, there's really three functions. Span of attention, visual, spatial activity, and executive function have all been shown to decrease. Now one of the key points about looking at this literature is that as we look at controls, they get better over time because they learn how to take the test and the subjects get worse over time. So that gap is actually more significant than one might think because you have improvements in the controls.

There's a lot of literature and talk about dementia. Dementia and cognitive change are two different processes really. Cognitive change from a therapy may be transient over the course of weeks and reversible upon stoppage of the therapy. Dementia, of course, is a life-altering, life ending illness that is chronic. And so these literature deserve some criticism, but it does suggest that long-term androgen deprivation therapy may be associated with an uptick in the risk of dementia.

Well, we proposed that there are patients who are at risk for dementia and we proposed that by studying the risks for dementia in our prostate cancer populations, we may be able to identify, through using a polygenic hazard score, those who are at risk as well as those who are protected. And that will be something where moving forward we would be able to assure patients that they are not going to be affected by the cognitive impairment that may arise from androgen deprivation therapy while focusing on how to improve the outcomes of those who are.

And in fact, with this conceptual framework, we think that there are multiple arenas through which the androgen deprivation is going to alter cognitive impairment.

So with Alicia Morgans, we are now about to launch a randomized trial (ARACOG) where we're looking at antigen receptor-targeted therapies in the form of enzalutamide and darolutamide, looking at cognition over the course of the spectrum of therapy with an opportunity for crossover for those patients on either arm of the study who experience a cognitive impairment as measured through the CANTAB study.

So I'd like to thank you for your time. I'd like you to think about #BenchpresstoBedside research in your own clinics. I'd like you to speak carefully to your patients about cognitive decline and not confound the data on dementia from the transient cognitive declines that can occur from oral therapies and to join us in this research efforts if you have the opportunity to do so. Thank you.