Bipolar Androgen Therapy for Prostate Cancer: An Alternative Approach

Brian McCloskey and Brad Power August 10, 2022 “It's been all upside. I'm living my best life right now on this treatment. ” Bryce Olson “There's no reason to be optimistic about this result.

Advanced prostate cancer patient Bryce Olson shared the story of his exceptional response to Bipolar Androgen Therapy (BAT), where high doses of testosterone are alternated with androgen deprivation therapy. Then Bob Gatenby, MD, commented on Bryce’s experience and strategy from his perspective as a leader in adaptive therapy -- using evolutionary and game theory to inform cancer treatment strategy.

Bryce’s Exceptional Response to BAT Bryce Olson has been heavily treated for his prostate cancer since his diagnosis eight-and-a- half years ago. He has had 12 lines of therapy, including the standard therapy of androgen deprivation since 2014. Somewhat out of desperation, a few months ago Bryce took a flier with BAT, flooding his androgen-deprived cancer cells with testosterone, which normally fuels cancer growth. 79. It's been all upside.

He’s living his best life – what guy wouldn't want testosterone? In addition, taking testosterone can restore sensitivity to hormone-blocking therapy again, creating the opportunity to cycle from providing testosterone to androgen deprivation therapy, an adaptive strategy. It's criminal not to scale this. What Does It Take to Choose BAT? First, most patients and oncologists are not aware of or considering BAT as an option.

Pharma won’t push this treatment that only costs $200. Second, the patient has to be brave enough – taking testosterone can be like throwing gasoline on the fire, feeding cancer growth. Third, the patient must find a doctor that's willing to support it. The Good News Bryce got the information and insights that predicted that this therapy would work. It has selected cancer cells sensitive to testosterone and done a great job of killing them.

It's a wonderful example of precision medicine. He looked at the evolutionary status of the tumor in a way that revealed an Achilles heel, and he attacked it. The Bad News Bryce's many treatments have made a mess of his tumor population, so no one knows what's in it, and that’s always a problem. What's almost certain is that there are cells that are resistant to what has been done. If there are still tumors, there is a small resistant population.

Flooding with testosterone is punishing the adaptive strategy to low testosterone. At some point, it's going to go away. There's going to be a new strategy that's evolving. Even cycling between supplying testosterone and depriving androgen will be selecting for androgen-independent cancer growth. There's no reason to be optimistic in the longer term. Prostate cancer is hard to eradicate. Strategy: What Should Bryce Do Next?

Humans think linearly, but cancer is a nonlinear system. It might seem that cycling on the hormone path will work, but it's very hard to predict. Bryce has put the tumor on the mat with BAT. He has a small cancer population, and small populations are vulnerable to extinction. But usually in evolution, the final nail in the coffin (extinction event) is not the same thing that drove the population down originally.

Should Bryce add a different therapy now when he has a small cancer population? The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

Meeting Notes SUMMARY KEYWORDS testosterone, androgen receptor, psa, patients, therapy, cancer, tumor, population, cycle, androgen, resistant, oncologist, point, cells, bryce, kill, line, liquid biopsy, stop, people SPEAKERS Jonathan Starr, Saed Sayad, Emma Shtivelman, Brad Power, Brian McCloskey, Bryce Olson, Rick Stanton, Ryon Graf, Bob Gatenby, Jim Ward Bryce Olson 00:03 Thanks for having me here. , Bipolar Androgen Therapy.

, but it wasn't even in the top five things for us to consider, partially because I think it's perceived as so dangerous. Throwing a bunch of testosterone into a guy is like putting gasoline on a fire. We never considered it even though it was in the back of my mind. I want to tell you about my success story with this and then talk about why I think it deserves more attention and scale. Bryce Olson 01:09 Is it a game changer? I think it could be.

T.? It's bipolar androgen therapy. It's designed to repeatedly shock the prostate cancer cells. You're alternating between a polar extreme of high and low testosterone levels. n Therapy” Bryce Olson 01:09 Is it a game changer? I think it could be. T.? It's bipolar androgen therapy. As you can see on the graph on the right-hand side of this Johns Hopkins study, they were using 30-day cycles, or 28-day cycles.

They would inject a patient with 400 milligrams of testosterone, and it would go up rapidly over the first two weeks or so, and then it would start to drop. This alternating pattern refers to supraphysiological T levels and then castrate levels. T. Bryce Olson To more easily understand this, I want to talk a little bit about baseball. Using analogies is always an easy way to think about things.

Let's talk a little bit about the androgen receptor and androgens in general, and we'll use a baseball analogy. Think of the androgen receptor which is on the cell surface of the prostate cancer cell. Your prostate cancer cells have androgen receptors on them, and they bind to androgens. Think of androgens as baseballs and androgen receptors as gloves.

When you get an actual binding, that's when it folds in the nucleus and starts to rapidly divide. That's what generates prostate cancer growth and PSA production. If you take away testosterone, which is what we do with anybody who's in stage four, you give them Lupron or Eligard, and you're taking away the baseballs, so essentially the gloves don't have anything to bind to initially.

It usually works for everybody for a little while and then cancer figures out how to grow despite having low levels of testosterone. The other way you can gum this up is using an anti-androgen like darolutamide, apalutamide, enzalutamide. Think of that as maybe throwing an orange into the glove. You gum up the receptor. That way a baseball can't bind into it. I'll say this again.

Think of androgen receptors as gloves and testosterone, essentially androgens, as baseballs because I'm going to use this analogy when I tell you about my story. Bryce Olson 04:54 Why was I a good candidate for this? I was heavily pretreated. This is my 13th line of therapy over the last eight and a half years. I've seen ADT since 2014, and I failed abiraterone.

I've already been on first line and second line hormonal therapies, and I'm castrate resistant. From a genomics perspective, you can see that I have AR copy number gain, so I have high levels of baseball gloves. When we took away the testosterone and then added abiraterone, that's when I saw the AR copy number gain show up. " I have high levels of AR. I also have a P53 alteration. T. I also shared ownership with my oncologist. Dr.

Rana McKay hadn't done this before with anybody. She wasn't going to do this unless I came in and said I wanted to do it. It was going to have to be a shared ownership between the patient and the oncologist because this is not being scaled right now. Johns Hopkins did it, Oliver Sartor has done a little bit of it, and maybe a couple of doctors across the country have done a little bit of this, but it's not being widely used.

It's going to require that the patient be brave enough. With testosterone in the equation, it can be like throwing gasoline on the fire. You must be brave enough to try it, and you must have a doctor that's willing to support it. I have a couple other quick notes that show how my treatment is different from the Johns Hopkins study. I'm doing this every six weeks, so I'm not cycling on 30 days.

I'm cycling on 45 days, every six weeks, and I'm adding pembrolizumab to it. The theory is that when you add testosterone in this type of a supra-physiological high-level way, you are turning on some of the immune function on the prostate cancer cell. I honestly don't know how much of my success is attributed to pembrolizumab versus testosterone, but I am using both. The other note is that I did have a major pain flare after the first dose.

As I have talked about this, it's been all upsides. What guy wouldn't want testosterone? I'm loving this therapy, but I did have a major pain flare up that was excruciatingly painful for about three or four days after the first cycle. When you read the Johns Hopkins patient guide about this, they talk about it. They say if you have bone pain from cancer, they don't really want people with bone pain to do this.

They consider you symptomatic, and they don't really want you to do it because they think it's going to be really painful. And it was super painful, but it went away. I did a high dose of steroids for five days, and then it went away. I haven't had it come back in the second and third rounds. I just want to throw that little note of caution up there. Go to the next slide. T.

These are all the different treatments that I've done and my resulting PSA afterwards. Everything from ADT, to chemo, to multiple PI3k inhibitors, Provenge, abiraterone, actinium in New York City, another PI3K inhibitor, and cabozantinib with carboplatin. " I was just waiting for something that could potentially save my life. Bryce Olson 09:39 This is what happened to me. T. with pembro and we measured it.

After the first cycle six weeks later, my PSA drops from 307 to five. 79. I do imaging after my second cycle leading into my third cycle. This is on the right-hand side. This is a PSM-PET scan. I want you to look on the left. Look at my legs, pelvis, and hip area. Look at my sternum and chest area and then look at my head on the left-hand side. Now look at the right-hand side. The lesions on the head are gone.

The lesions on the chest are going away - it's lighter. Look at the pelvis and the legs. Look how light it is. That's PSMA uptake. It's literally starting to erase from my body. I used to have pain in this area, I was even a little bit wobbly when getting up off the couch. It's all gone. All that's gone. I don't feel any pain. I don't feel anything bad. From chemo and actinium, I had nearly permanent nausea and fatigue. I had no appetite.

I lost 20 pounds; I went from 170 to 150. I was really going into a bad spot. I got rid of all that. I have no more nausea. I have no more fatigue. I have an appetite now. I have more muscle mass. I got to 170 again. I'm not even exercising but still gaining muscle mass just from testosterone. Sex is better. It's all upside. Please go to the next slide. Bryce Olson 11:45 Here are some other study results.

I took a picture of the actual patient guide. If you want to Google it you can download it and read it. PDF and put it in the notes too for people that want to read about it. There were four Johns Hopkins studies on this. What they show in the studies is that patients fell into three categories. They either had a PSA response, and that response was usually a 50% drop.

They saw on scans that some of the cancer was going away which lasted for months. There was a PSA-stable cohort as well. Patients that had a little bump in their PSA, but then it flattened out, and they didn't progress. They just kept them on that as well. There was also a cohort of folks that progressed. Their PSA went up right away. It didn't work at all.

But in patients with CRPC that were progressing on Xtandi or Zytiga, about 33% had a PSA or an objective response after three cycles. That duration, on average, was about six months. T. It's a twofer. , which in my case, had this dramatic response. I'm re-sensitizing myself to hormone therapy again so I could redo this. That's what's cool about this.

T right now, but if I start to get a rise in PSA and start to progress on imaging, I can go back to Zytiga or Xtandi and get some more mileage out of this. You can read about some examples in the report. , and then they went to Xtandi again. This should never work right? Once you build up resistance to Xtandi, it shouldn't work. , and then Xtandi again, 70% of these people had a PSA response with the rechallenge.

, 25% would have a PSA response and the time to progression was four months with their overall survival at 29 months. T. and then did Xtandi, 80% had a PSA response, and time to progression was 11 months. They had a 37-month OS. That's super cool. , and you get re- sensitized to some of these second line hormonal drugs, so you just get extra mileage. Bob Gatenby 15:22 Congratulations on a very thoughtful and well-designed strategy.

It illustrates the point that if we understand the underlying dynamics of cancer, we can develop therapies that are based on that even far into the disease. We have a protocol with patients just presenting metastatic prostate cancer. We do androgen deprivation therapy, but we do it with cycling. We cycle based on the PSA. Basically, when the PSA goes below 50% of its pretreatment value, we stop and then let it come back.

What we've learned from that is that the body begins to produce testosterone very quickly after that and continues to do so. We have patients who continue that for nine years. They are still on it after nine years. That's fairly simple, on-off, on-off, but guided by the dynamics of the patient. We don't force it arbitrarily, just on-off at three months or four months. We're watching. We're letting the tumor tell us when to do it.

You're far into this process.