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Alicia Morgans: Hi, I'm so excited to be here today with Professor Sam Denmeade, who's joining me from Johns Hopkins University, as well as at ASCO 2024, where he is recapping a wonderful presentation that he gave on Bipolar Androgen Therapy and the TRANSFORMER study, looking at molecular markers of response. Thank you so much for being here.

Samuel Denmeade: It's great to be here.

Alicia Morgans: Wonderful. So Sam, we've talked a few times about BAT or Bipolar Androgen Therapy. We've also discussed the TRANSFORMER trial, but not everyone may have seen those videos. I wonder if you could share a little bit of background. Tell us about the TRANSFORMER trial before we jump into what you presented at ASCO.

Samuel Denmeade: Sure. So the TRANSFORMER trial was the largest trial we've done with this approach called Bipolar Androgen Therapy, which is basically the concept of giving a man who's resistant to lower hormone agents high doses of testosterone in a kind of pulsatile way. So, the TRANSFORMER study was a randomized study. It was about 200 patients. Half of the patients got treated with testosterone, and half of the patients got treated with enzalutamide. So, kind of a weird study because it compared two exactly opposite treatments. The endpoint of the study was to see if the testosterone worked better than enzalutamide. What we found is, very interestingly, they worked the same. We had the same response to testosterone as to enzalutamide, with the same duration of response, which was about six months.

The other thing we saw was that after the patients got testosterone or enzalutamide, they were able to cross over to the opposite treatment. In those patients who got enzalutamide initially, we had about a 20% response that lasted about three or four months. In the patients who got testosterone first and then enzalutamide, we had about an 80% response, and that lasted about 11 months. So, longer response and more people responded. We're very excited about that sequential approach. From the TRANSFORMER and all our studies with testosterone, about 30% of the patients respond with PSAs going down, which is the typical kind of response we see in prostate cancer. So, we've been trying to figure out, "What is it about those patients? Are there markers we could find that would predict who responds and who doesn't?"

We've looked at biopsies of patients where we grind up the tissue and look for markers. We've looked at models that we grow in the lab, but we needed a test that would be easy to do. What I'm presenting here at ASCO is the results of a blood test we developed where we look for DNA in the blood. The amount of DNA and the kind of DNA in the blood potentially can predict response. In this case, we found that the androgen receptor, which is the target of testosterone and also the target of our androgen-blocking drugs, if it was quite high, lots of androgen receptor, it seemed to predict that those patients responded better to testosterone. When it was low, the patients would respond better to enzalutamide. So, it potentially is a blood marker we could use in the future to stratify patients in terms of high testosterone or low.

Alicia Morgans: Thank you for recapping the study and certainly for sharing some of the data you presented in your presentation at ASCO. I wonder, are there any other characteristics beyond this, or do you think this is going to be sufficient to potentially identify those patients for one treatment or another?

Samuel Denmeade: We've tried to look across the studies we've done at a lot of different things, and so far, the only thing that's really popped out is the level of the androgen receptor.

Alicia Morgans: Yeah.

Samuel Denmeade: We've looked at, "How high does the testosterone go? How low does the testosterone go? How old are the patients? Do the patients have other mutations?" And really, nothing else has stood out. So, it could be the best thing we have. PSA is a very complicated marker for testosterone treatment because testosterone directly stimulates the cancer to make PSA. So, even if the cancer doesn't grow more, it will make more PSA, which can complicate interpreting whether it's working or not. So, we definitely need something else. This looks to me like something that we're going to be doing more and more in cancer treatment.

Alicia Morgans: Yeah.

Samuel Denmeade: It will probably become a mainstream test, looking at DNA in the blood across all cancers. So, we're hoping to be able to build on that for this particular kind of treatment.

Alicia Morgans: Absolutely. And where do you think you go from here? Because, obviously, I think the TRANSFORMER results were really provocative, and certainly if you have a way to identify those patients who may have the biggest benefit, like this blood-based ctDNA type of approach, you can imagine that you could design future trials or treatment strategies to potentially capitalize on this.

Samuel Denmeade: Yeah, so one of the visions I have is as a patient is on hormone drugs that lower testosterone, we could serially sample their blood. When we see that this marker starts to increase, it could indicate now's the time to switch from low hormone to high hormone. It also will help us potentially in future studies by selecting patients better to show a better response and help us maybe with some combination treatments we're trying to do to figure out who are the best patients to treat. One, to get a better response, and two, to have patients avoid any toxicities that we might see. There's also some potential where there's been some data that very high AR levels may predict resistance to lots of treatments, not just androgen therapy or hormonal therapy, but also chemotherapy and radiopharmaceutical therapy. One idea would be maybe we can give testosterone first, lower that AR level, and re-sensitize not just to enzalutamide or other anti-androgens, but maybe to all treatments.

Alicia Morgans: So, to that point, in your first example, do you have good evidence that over time there is a dynamic quality to this particular marker, that with continued exposure to an AR pathway inhibitor, for example, that marker is going to go up, or potentially with continued exposure to testosterone or BAT approaches, that it comes down?

Samuel Denmeade: So we haven't done it with this blood marker. We've looked at it in biopsies, and what we see in the biopsies is, at the beginning, when patients have been on hormone-lowering drugs, the level of the androgen receptor goes up substantially, maybe a hundredfold or more. So the cells really, really like the androgen receptor to be there, so they make a lot of it. We found after months of treatment with testosterone, again in repeat biopsies, the level drops significantly, and we think that's what sensitizes the patients to re-exposure to anti-androgens. So now, in a future study, we're hoping to show that with this blood marker that it's dynamic, we can see it in the blood, so we won't have to biopsy patients over and over again. We can have this marker that we can use every month or every other month, which might show us how dynamic this is.

Alicia Morgans: I think that's a wonderful idea. I definitely look forward to your next study where you're showing us how this can happen and how it could be utilized. Now, for those who have questions about the safety of this kind of approach, and I know we've talked about the safety seen in the TRANSFORMER trial before, I wonder if you could just remind everyone what were the adverse events of concern? How did you keep patients safe? What are your thoughts on that?

Samuel Denmeade: So the very first thing to stress is there is this potential for testosterone to cause worsening pain when you first get it. And so, we were very careful about selecting patients who had no pain, particularly from prostate cancer in the bone. So that was a very hard stop; you couldn't be on the trial. We've had a few guys slip through the cracks and get testosterone with pain that we thought might've been arthritis, and the pain gets worse. So that was one safety feature that we tried to avoid. Otherwise, it was pretty well tolerated. I would say most of the side effects were very low grade. The big things we saw were some swelling in the lower legs. Some men noticed some tenderness in their breasts. Some men had kind of an achy feeling when we first gave the testosterone to people. The weird thing is we don't really have good parameters for the good things that we saw.

So we focus in cancer a lot on all the side effects because all the drugs cause side effects. This is kind of a unique therapy because it actually makes people feel better. We don't have a good scale for that. So we saw men have improvements in fatigue and just overall energy and strength and sexual function, and we don't have a good grading system for that. So those are favorable things we saw. We see blood counts get better. So there's a lot of really good things that happen. And I would say overall, we also did not see... One concern we had at the beginning was that it would make the cancer grow much faster. We really don't see that at all. We see that the patients either have stabilization of the cancer or regression of the cancer, so that was exciting. And kind of the paradox of this treatment is that everyone would've thought it would've made it worse, sort of gasoline on the fire, so to speak, but we definitely did not see that.

Alicia Morgans: Well, reassuring to say the least. So if you had to give a final message based on your presentation at ASCO 2024, what would that message be?

Samuel Denmeade: Well, I think this is kind of a new treatment that goes against the normal paradigm, and so we are trying to figure out how to get it into the mainstream of treatment. I think patients who might be interested in this really should talk to their doctors about it. There are patients out there that I know of who are doing this on their own. So my message would be, "It's an interesting idea. It does seem safe, but it's in your best interest as a patient to talk to your doctor about it. And if your doctor is not familiar with it, have your doctor reach out to someone like myself or others who are familiar with it before you go down the road of using it."

Alicia Morgans: Okay. Well, thank you for advancing something that makes people feel better, and certainly also simultaneously trying to make sure that everyone stays safe. So I really appreciate your time and your expertise. We look forward to continued studies and learning from you.

Samuel Denmeade: Thank you.