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.
Testosterone therapy to... LOWER testosterone production?
