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.
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.
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.
Not only is there no way to choose responders from non-responders, but even though it extended the potency of Xtandi after Zytiga, there was no significant increase in survival. Still there was a QOL benefit for some while it lasts.
Maybe it would on a larger study. Or maybe the cancer catches up by enlisting compensatory mechanisms. Although we are usually focused on the role of the androgen receptor (AR), there is much more to prostate cancer's development than just the AR (which is very much Dr. Sartor's point)
This is an excellent avenue.. I hope I'm a responder. About 18 months ago I started 400 mg weekly cypjonate injections. My PSA is fluctuating at low levels and last measurement was 0.039.
My MO is SOC and was very against it but after 9 months she didn't express any reservations.
My last thought is that if you've been an athlete for your entire life, the quick end to that on ADT destroys you mentally. Sometimes you would rather die than go on as less than what you were. Athletitisicm ends sometime but it should be a gradual decline from age rather than a sudden unnatural end due to hormones.
QoL means different things to different people and I both acknowledge and respect that. Fortunately my MO is intelligent so understands this.
I had my 6 month consultation with Sartor in NOLA last week. With my PSA detectable again after years of being undetectable we discussed possible options going forward should it continue to rise. BAT was one one of them, at the top of the list. He said I would be a candidate, given my low PSA, age and the fact I am asymptomatic, and good physical status. He wouldn’t offer it to someone who doesn’t fit that criteria. He went on to say he feels that he has a good handle on it and knows what to do if he determines a patient is not responding or is having an undesirable response. He has had quite a few patients who have done excellent on it for extended periods, had improved QOL and were able to successfully rechallenge Xtandi after receiving QOL. I plan on giving it a shot should my situation warrant.He is also overseeing 3 other trials at Tulane, some pretty exciting stuff, that would also be options for me going forward. 4 cutting edge clinal trials under his stewardship is pretty impressive.
He said to look for some good news on the coming weeks regarding PSMA scans from the FDA and also on Lutetium in early June, he sounded very positive on Lutetium, he is overseeing a trial arm at Tulane. Exciting stuff, he’s a brilliant guy, I left there pretty jacked.
BITE AMG160 therapy, ARV 110 therapy and Lutetium. I’m planning on getting Provenge this summer which he was in favor of especially since I still have my port from chemo. When I asked if BITE (another form of immunology) would be cancelled out by getting Provenge he said not at all since the two work totally different.
Dr. Sam Denmeade, in the recent TRANSFORMER paper [1], opens with:
"Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment."
I remember the days before the term "castrate resistant" was coined, when the PCa literature stated that ADT failure was due to cells no longer needing androgen. The realization that the androgen receptor [AR] axis remained active in most men who failed classic ADT, led to the development of Abiraterone (the scorched-earth attack on steroid hormones).
In Johann de Bono's Abi paper [2] - now ten years old - we discovered that:
"After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months ..."
A mere 3.9 months! It was considered to be a big breakthrough. And, of course, the study was on men with CRPC who had already received chemo and had no remaining options.
In TRANSFORMER, radiographic progression-free survival was 5.7 months in the BAT arm. At least as good as switching to Enzalutamide, but I sense a continuing negativity towards BAT in certain quarters.
Dr Oliver Sartor was naturally interested in the difference between responders & non-responders. Perhaps with Denmeade's adaptive upregulation of the androgen receptor in mind, he looked at the AR axis, but it seems that what distinguishes the non-responders is non-AR adaptations.
In post-Abi CRPC cases, there seems to be a 25-30% response to BAT. I wonder how that compares to CRPC cases who have not received 2nd-line ADT? It seems to me that the harder we attack the AR axis, the more likely we are to select for cancer that no longer needs androgen.
There is an obvious need to develop therapies that can significatly extend life for men with CRPC. But there is an equally urgent need to find a way to prevent CRPC from occurring. Perhaps BAT will be part of the solution?
I think BAT is being used more and more as another arrow in the quiver of clinical management. It is practice, not trials that will determine where this may go. To anyone doing a supra T treatment, write about it. Good and bad, that is vital info.
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BAT (Bipolar Androgen Therapy) 
Could BAT be our last chance?
Genomic and genetic testing
