Baseline Pathogenic Mutations in Metastatic Castration-Resistant Prostate Cancer Patients Being Treated with High-Dose Testosterone - Oliver Sartor

March 28, 2021

Oliver Sartor, MD joins Alicia Morgans, MD, MPH, and discusses baseline pathogenic mutations in patients who are getting treated with high-dose testosterone. Beginning with a background highlighting the TRANSFORMER trial, A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men with Castration-Resistant Metastatic Prostate Cancer, Dr. Sartor explains the challenge in this trial in determining clinical characteristics of who might benefit and who might not benefit from high-dose testosterone. In the abstract being discussed, which was presented at GU ASCO 2021 a responder, non-responder analysis was performed to better understand the role of pathogenic mutations in ctDNA as a predictive biomarker for patients treated with high dose testosterone. AR and TP53 pathogenic mutations are common in both responder, and non-responders but other pathogenic mutations are more common in non-responders. This study looks at genetic pathways outside of the AR/TP53 axis and if they can drive resistance to high-dose testosterone.


A. Oliver Sartor, MD, Professor of Medicine and Medical Director, Tulane Cancer Center; C. E. and Bernadine Laborde Professor of Cancer Research, New Orleans, Louisiana

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a good friend and colleague Dr. Oliver Sartor, who's the Laborde professor of cancer research and the medical director of the Tulane Cancer Center in New Orleans, Louisiana. Thank you so much for being here with us today, Dr. Sartor.

Oliver Sartor: Thank you, Alicia. My pleasure.

Alicia Morgans: Wonderful. I wanted to speak with you a little bit about a presentation that you recently had at GU ASCO 2021, a poster on baseline pathogenic mutations in patients who are getting treated with high-dose testosterone, which is really a fascinating approach to therapy for our mCRPC patients. Can you tell us a little bit about this work?

Oliver Sartor: I can, and first of all, I would like to give a little context because I think that is important. The group at Johns Hopkins and I really want to give them credit. Sam Denmeade and colleagues have pioneered the use of high-dose testosterone or bipolar androgen therapy as they often refer to it in terms of metastatic CRPC treatment. And this of course is the antithesis of logic. You know, you start off trying to get testosterone down to zero with things like abiraterone, block the antigen receptor with things like enzalutamide, and darolutamide. And here we are talking about making the testosterone very high. What they use as testosterone cypionate, typically, at 400 milligrams, IM about every four weeks. That will take the testosterone to well over a thousand and then it will come down almost to a castrate range or to a castrate range in many patients after about four weeks and see bipolar androgen therapy.

Oliver Sartor: Those guys put together a trial called the TRANSFORMER Trial. Tulane was a participant in the TRANSFORMER trial. And that is now under review at a major journal. And what I will say is that I think there was a lot of surprise information when these data were initially presented in various forums, like the PCF, et cetera. And what it showed is that the high-dose of testosterone could actually have a positive effect on a substantial subset of patients. Well, in part of the trial, we were aware of these positive findings and have been exploring the use of high-dose testosterone in our patient population. And one of the things that had been a little bit frustrating is to try to determine who might benefit and who might not benefit. And we couldn't just look at anybody and tell, what were the clinical characteristics?

Oliver Sartor: We couldn't really pick it out. So what we did in this particular abstract is we took up patients that I'm going to call responders. And then we took a group of patients that we called non-responders. I think we ended up with 17 responders and about 21 non-responders. The definition of response was the individuals who received at least three cycles of the therapy and had a decline in PSA of 50% or greater. So these are individuals, the PSA goes down when we give them the testosterone and they do it for a little period of time. And it turns out, by the way, the response rate is probably somewhere between 25 and 30% in our experience, in the TRANSFORMER experience. And then, on the other hand, we had another group of patients that would not respond and their PSA did nothing but go up. And they typically had just two cycles of the therapy and then stopped.

Oliver Sartor: So this is a responder, non-responder analysis. And we have [03:46 inaudible] strictly, in tumor DNA, we were using the Guardant360 platform which is pretty good for AR and of questionable completion for the rest of the genome. We have to realize that strictly in tumor DNA doesn't mean you are measuring everything. And the deletions, potentially things like RB deletions and P10 deletions may be hard to detect and [inaudible 00:04:10]. But the bottom line is we look at the difference between these responders and non-responders, so that is what the poster is about.

Alicia Morgans: Wonderful. And did you end up finding that there was an association between these abnormalities in the genes and their response or non-response?

Oliver Sartor: We did. So, first of all, we have to state that this is very preliminary information. This is the first analysis we have done. It was not done prospectively, although the data were collected prospectively, it was analyzed retrospectively. So, always the little caveat with these types of analysis. But what we found was that there was no difference in the AR either amplification or mutation rate between the responders and non-responders. I was thinking initially, well, maybe those individuals with an amplified AR may do better with [inaudible], or maybe those individuals with a mutation may do better. We really could not find that to be true. And there's been a fair amount of data published on P53 and P53 is very commonly mutated in these patients. So we did a P53 analysis. We couldn't find anything P53.

Oliver Sartor: So, we were scratching the head a little bit, but one of the things that we can find in these panel tests, where we are actually looking at about 84 genes, we can look in the rest of the alterations in addition to AR and P53. And what we found was interesting.  There was a statistically distinct difference between the non-AR, non P53 mutated genes as in lower incidents of these in the responders, as compared to the non-responders. Here is where I think we may sum it up, and this is conjectural. So, please realize that I'm raising a hypothesis. I am not stating a fact.  We would hypothesize that these mutations, outside of the AR and P53 axis are the ones that are driving the progression of the high-dose testosterone. So in other words, the genes like Mek or the genes like P10 or the genes that might be coming in, even EGFR or some of the RAF genes, if these abnormalities outside the AR P53 axis are the ones that are driving progression.

Oliver Sartor: And I think in some ways it does make a little sense. Imagine for a brief moment that the guardant variety sort of hormone-resistant, castrate-resistant cell is going to be harboring these antigen receptor alterations. So we know that they are important and we look at some of [inaudible] data and stuff that you assume with ARP110, et cetera, but there are things going on outside of the AR access. So we've got to pay attention to those too because this is where escape occurs. Not everything is AR sensitive and these non-AR sensitive non AR genes, may be the ones that are important. Anyway, that is what we would hypothesize. And it's at the very first beginnings, still being examined.

Alicia Morgans: I think that's fascinating though, and a really important reminder to all of us that although we have been so focused on the AR and for good reason because even when we thought these cancers were hormone-resistant, back when we used that kind of language for these tumors, we found that even further suppression or targeting against the AR was actually incredibly effective in that castration-resistant setting. So, having these other, thinking about these other escape pathways, I think is so important, and it also makes some sense when we think about it, as you mentioned, the response rates being maybe in the 30% range. I mean, if everything is based on the AR why would that only affect 30% of patients if everything was based on that kind of an approach or certainly P53, which is also present and probably more than 30% of patients.

Alicia Morgans: So, that all makes sense and is, as you said, really thought-provoking. Now how are you going to continue to study this? Are you... You mentioned the TRANSFORMER study, which I think is at this point, it is fully accrued. And hopefully, we will hear some data on that at some point. Is this something you can look at in that data set or in others to continue to investigate?

Oliver Sartor: Well, the assay is we are not going to be similar between the TRANSFORMER and our subset analysis on our own data set. Remember this is from our data set that we've done here at Tulane. But one of the things I did want to point out is if you want to come up with an enzalutamide response rate after abiraterone progression, what is it? About 30%? So, there is something, I think about 30% of these patients that may be manipulated. By the way, one of the important findings from the transformer study is that after the use of testosterone, you can re-sensitize to things like enzalutamide, and you can come back with the enzalutamide and get a very high response rate. And that is a different subset analysis. But, by the way, keep your eyes open for that on the TRANSFORMER trial, because the re-sensitization of these patients to AR targeted therapy is something that's quite important.

Alicia Morgans: And I think it will be super important to patients too. And your work and understanding which of these patients may actually respond versus which may have no response or even disease progression in the setting of testosterone, I think is going to be really critically important too, as we try to ultimately integrate those findings if they end up being such that we could change the standard of care eventually. So, if you had to summarize this work that you've done, really exciting work on this bipolar androgen therapy type approach, which everyone is really enthusiastic about now, especially patients, what would your summary be?

Oliver Sartor: My summary would be that looking at AR is insufficient to be able to predict the responsiveness to the testosterone or not. I think we are going to have to look not only at AR but outside the AR axis. And P53 is very common and seems to be outside the AR, outside the P53 axis. And all of these other mutations that we see are potentially important. But there is much more to learn. And I think that is probably the most important thing I can say is, oh my goodness, we have so much more to learn.

Alicia Morgans: We always do, but, this is just the beginning. And we find that these may be pathways that are important in this high-dose testosterone setting. Well, maybe they are also important for other therapeutics that can be designed to target these particular escape pathways. They may be useful otherwise as well. So, thank you so much for all that you've done. This work and for taking the time to present it today, we really appreciate your time and your expertise.

Oliver Sartor: Thank you, Alicia. Again, my pleasure to be here.