Alicia Morgans: Hi, I'm so excited to be here today with Dr. Sam Denmeade of John Hopkins University. Dr. Denmeade has really innovated the bipolar androgen therapy, which is really introducing testosterone into patients who have metastatic prostate cancer to help them really have a nice response, hopefully, from that added testosterone, plus all the other benefits that one can get. Importantly, there are risks, there are benefits, and there are specific areas where we should use this approach and other areas where it's not the right thing to do. So, I'm excited to talk to Dr. Denmeade all about it today. Thank you so much for being here with me.

Sam Denmeade: It's great to be here.

Alicia Morgans: Wonderful. So Sam, I wanted to hear a little bit about this bipolar androgen therapy, BATs. What exactly is it? Can you give the patients a little bit of an idea of what it means when we say that?

Sam Denmeade: So, bipolar androgen therapy is an idea we came up with based on what we know about prostate cancer and how it gets resistant to all the hormone therapies we use, which lower the testosterone in the body, block the testosterone in the body. And what we discovered was, paradoxically, when those cells get resistant, if you do the exact opposite and flood the cells with testosterone, those cancer cells can't handle that either. So, they don't like it when it's too low and they don't like it when it's too high. Based on that laboratory work, we came up with this idea about maybe we could inject patients with a lot of testosterone who've become resistant.

We were quite surprised to see that, one, it was pretty safe to do, a number of men responded very well to it. Some men felt really good to have their testosterone restored in terms of just their life quality based on functional capacity, sexual function, lots of different things improved. And we saw that the biology we thought was in play was what was happening. So, patients who were very resistant to hormones for a long time seemed to respond. The cancer seems to be able to respond to its environment. So, the cells that survive after going in low testosterone for a long time set themselves up to almost be overdosed with too much.

On the backside, we found after giving testosterone for a while, to our surprise, that the cancer cells become sensitive again to hormone therapy. So, we've been able to go high and low and high and low, and we have a study now where we're looking at, can you do that over and over again, maybe for a very long time. So, it was a surprising result, but I think it was based on a lot of good science before the studies we did.

Alicia Morgans: I think it was definitely based on a lot of good science. You and your lab have been investigating this really thoroughly for many, many years. And just to emphasize, this is patients who have been on hormonal therapy, they are then given high levels of testosterone for a period of time, and then they're given another androgen suppressor or testosterone suppression type treatment. And then, this oscillation, this back and forth, or bipolar approach, is what seems to get this response. And some patients seem to actually feel better because of those doses of testosterone.

Sam Denmeade: Yes, that's correct. Clearly, this is a therapy for a certain stage of the disease. So, patients who have not had any hormonal treatment, probably the opposite would happen. If we gave testosterone, we might even make it worse. So, certainly in patients who haven't had local treatment for prostate cancer, it's not the right thing, or who haven't had hormonal treatment yet, hormone lowering treatment. We think there's the stage of the disease where this is appropriate, and those are the patients we focused on in all of our trials.

We've also found patients who have a lot of symptoms from prostate cancer, particularly pain, this is probably not a good idea. Because, when we first give the testosterone, people can have what we call a flare where the disease could not necessarily grow but make factors that can make pain worse. So, we found that in guys who have pain already, few guys that we treated, the pain gets a lot worse. People that don't have any pain seem to do fine, and that's the majority of the patients we've treated. But clearly, I get asked a lot of questions from people around the world, that's really the place that this is for patients who've become resistant to their primary hormone therapy, their second hormone therapy that we use, that's the group we look at.

Alicia Morgans: Okay, great. I wanted to talk with you a little bit about some of the benefits, because I did see a paper that suggested that some of the physical vitality of patients could be maintained, maybe their muscle mass or their physical functionality. And we know that, when we lower testosterone levels, in some men we can induce almost a frailty type phenotype-

Sam Denmeade: Correct, yes.

Alicia Morgans:... that we can see in older adults in geriatric literature. And that certainly is not what we would want. Patients are at risk for falls, they lose muscle mass, among other things, and generally can have this failure to thrive. So, the patients in the study that you put together, and it was a compilation of a couple different populations that you had studied, seemed to have some prevention of that loss of muscle mass and other loss of vitality. Can you speak to that a little bit?

Sam Denmeade: Yeah, so we've looked at this in two ways. On the studies we've done, we looked through questionnaires to patients just in terms of how they experience the testosterone. The obvious thing we saw is men's sexual function can improve. They've been castrated or lower testosterone for a long time. That gets better. They have more interest in sex. Some men can have erections again. Those kind of things can happen. People also report, again, this vitality idea about they feel like they want to do more things, and go out with their family, and participate in things. They feel like they have more energy to go to the gym again.

And then, more concisely, we looked at patients' CT scans to see, are we changing actually some physical characteristics? And what we found was, after a couple months, we saw a pretty good decrease in body fat and an increase in muscle mass in these patients, which probably relates to this increasing functionality that they feel like they can exercise more and have more activities than before. And it's not in everybody. Some patients don't feel better, but a lot of the guys really... Sometimes, they don't want to come off the testosterone, because they feel so much better. So, that's been a very satisfying part of this treatment is to give something to people. As an oncologist, most of the things we give people make them feel worse. Here's an example of something you can give that makes them feel better in some cases.

Alicia Morgans: That is a great point. We, as oncologists, are often walking this line between deciding, do we want to control the cancer or do we want to improve quality of life? And this type of approach is one that may be able to combine the two, at least in some patients, which is really, really exciting. But one point I want to ask about and emphasize, do you do this in standard practice? Or you mentioned a clinical trial, should patients try this at home, in other words?

Sam Denmeade: That's a good question. I mean, we have a number of trials at Hopkins. We're not in China and Europe and Malaysia and all these places where people call me and email me. So, what I've done is I think we've generated enough data now, from a safety standpoint and how well does this work standpoint, that if patients reach out to me I work with their physicians and try to educate them. We've recently written a couple different reviews. One is for the patients to explain this. One is to help the physicians be able to talk to their patients about this approach. So, I have treated people off of study. Again, based on enough experience, now we've treated several hundred patients that I feel like those patients who have access to this, who want to try it. But again, making sure their physicians understand these issues about pain and other limitations of the treatment, like the right stage of the disease, et cetera.

So yeah, it's an easy thing to do. The testosterone is very inexpensive. It probably costs $20 a shot, so it's very inexpensive. So patients, even if their insurance won't pay for it, can try it. And sometimes patients write us back and tell us they've had great experience, and that's hope. For now though, I've been trying to do the best I can to educate everybody about making sure it's the right group, the right timing, and the right symptom complex.

Alicia Morgans: Absolutely. And really, with the assistance of a local doctor who also feels comfortable, understands all those risks, and is overseeing and caring for that-

Sam Denmeade: Yeah, so I've made myself, right now at least, the clearing house for this. I tell the physicians they're welcome to email me with questions. The treatment itself is very simple. We've published on it and it's not a complicated treatment. So, I try to help them as best I can. And now, we've written these things that maybe they can even have references to go to. Our ultimate goal would be to get this as a approved mainstream treatment. That's a little bit complicated, because it's a generic drug that there's certain financial issues related to getting a drug approved that will be hard to overcome. But I think, as we get enough data, we'll likely get it more in the mainstream. We're testing a lot of different aspects of it now in terms of how to combine it, what's the best way to give it, what's the right dose. Those things are coming too. So, more to follow.

Alicia Morgans: Wonderful. Well, I think that this is really something that certainly is exciting to patients. I think that doctors are always eager to learn more. And knowing that they have a resource in you, and also that you have published resources for patients as well as for clinicians to really wrap their heads around the data that supports this, is so, so important. And I do look forward to hearing where things go. And to patients out there, don't try it on your own, work with your doctor. But you know have a resource here, and of course those resources that are published. So, this is something, if your doctor is in agreement and you feel comfortable, might be important for you, with caution of course. Thank you so much for your time and for your expertise.

Sam Denmeade: Appreciate the time with you. Thank you.