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Alicia Morgans, MD, MPH, and Samuel R. Denmeade, MD, on Prostate Cancer: Results From the TRANSFORMER Trial

2024 ASCO Annual Meeting

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Alicia Morgans, MD, MPH, of Dana-Farber Cancer Institute, and Samuel R. Denmeade, MD, of Johns Hopkins University School of Medicine, discuss a study showing that patients with metastatic castration-resistant prostate whose disease is progressing on abiraterone with androgen-receptor alterations detected in the blood may benefit from bipolar androgen therapy. Routine liquid biopsy testing may enable further adoption of bipolar treatment (Abstract 5003).



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Alicia: Sam, thank you so much for being here with me today. It's really exciting to talk with you about the transformer study and some of the correlative investigations that you did within that study. Can you share a little bit about it? Samuel: Yes. Thank you for having me. The transformer study was the largest study that we've done of a new concept called bipolar androgen therapy, which involves giving men with castrate-resistant prostate cancer high doses of testosterone as a kind of counterintuitive treatment. The transformer study was a randomized study looking at comparing testosterone to enzalutamide, and we found some interesting results. There was a similarity in the response to both of those agents, even though they're distinctly the opposite of each other. There was a potential for testosterone to enhance response to enzalutamide in a crossover that happened. And so, we saw some very exciting improvements in the duration of responses. The response rate is about 30% to testosterone, and we've been very interested in trying to figure out who responds. And so, we've been looking at different biomarkers of response, both in tissue that we biopsy and in the blood. So, we have a presentation where we looked at CTDNA, and we found that in patients who had a very high level of androgen receptor in the blood, they seemed to respond better to high-dose testosterone. And patients who had low level of AR level in the blood responded better to enzalutamide, which kind of goes along with the laboratory work we've done, supporting that kind of hypothesis that we have of why this works. Alicia: That's great. I really want to pull out a couple key points. One, I think it's really fantastic and so exciting to think that exposure to high-dose testosterone may almost prime a renewed sort of sensitivity to enzalutamide, which I think, from a clinical perspective, would be interesting to patients, and is really fascinating from a biologic perspective. And I wonder, as you're talking about increased androgen receptor, do one of those treatments, either testosterone exposure or enzalutamide exposure, change the way that we see androgen receptor expression? Samuel: Yeah. So, when we treat a man with hormonal therapy for prostate cancer, eventually, everybody gets resistant, unfortunately. And it looks like a major driver of that is massive increase in androgen receptor expression. And we're trying to take advantage of that with testosterone, because we find when you have that massive increase, the cells become vulnerable to too much testosterone. They almost overdose on it. And in response, they dial the androgen receptor back down to baseline, and that seems to make them sensitive again to enzalutamide, or other types of anti-androgens. Alicia: Yeah. Samuel: So, one idea we have is could you go back and forth? Give testosterone for a while, give anti-androgen for a while, and we're studying that in some other studies that are ongoing now at Johns Hopkins and other places. Alicia: And I think from a patient perspective, it's certainly of high interest, and I also think it would be really of high interest to be able to test a blood-based biomarker to understand kind of where a patient is in that expression pattern, up and down regulation, to try to make a decision related to, should I consider enzalutamide or some AR pathway inhibitor, or should I consider high-dose testosterone. Is this something you see might be coming in the future? Samuel: Yeah, so our vision would be we could draw a patient's blood and stratify. Should you go on more hormone-lowering drugs, or on testosterone? That's one possibility. The second possibility is as we treat with one or the other, if we could see dynamic changes in the blood, that would suggest, okay, it's time to switch to the opposite treatment. That would be very maybe favorable for enhancing the response. So, we would know the right timing. Right now, we're kind of guessing a little bit. When is the right time to switch? Alicia: Yeah. Samuel: But if we had a marker that we could follow, and the marker now, the CTDNA marker, is becoming more and more, almost a standard test that we think is going to probably be, across cancer, patients will be seeing that a lot more. Alicia: Yeah. I think, you know, there are so many times where we are operating in the dark. And so, having the opportunity to use these CTDNA markers, like you explored in this analysis, would be so helpful for patients. Just as a final thought, you know, testosterone is certainly available. People can prescribe it. Is this something that you advocate people doing off of a clinical trial? Or, I guess I should say, are there safety considerations if someone is doing this off of a clinical trial? Samuel: Yeah, so the biggest consideration is we think when we give testosterone to men with prostate cancer, it's very safe. The safety features have been fine. However, if a man has pain, primarily from bone pain from prostate cancer, we have seen an enhancement of pain. So, we really advise people, if they have any pain from prostate cancer, do not try this. And it really is designed for men who have metastatic, castrate-resistant prostate cancer, not castrate-sensitive cancer. Because those patients, it may actually make the disease grow better. You know, there is a timing to this that it's not for everybody. Alicia: Okay. Well, great. Well, I so appreciate you taking the time to walk us through that presentation, and really to share with us some of the future possibilities that might exist. We always appreciate talking about your work. Samuel: Thank you very much. I've enjoyed it, speaking with you.

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