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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 talk today with Dr. Eleni Efstathiou, who is an Associate Professor of Medicine and a GU Medical Oncologist at MD Anderson. Thank you so much for being here with me today, Eleni.

Eleni Efstathiou: Thank you so much for having me, and it's always wonderful to be in the presence of a wonderful host and a colleague I really look up to.
Alicia Morgans: Oh, well, thank you. Well, the feeling is certainly mutual, and I really look forward to you teaching us a little bit more about the CARD study, which continues to give us insights, as we think about the treatment of men with advanced metastatic CRPC. Your team presented some really fascinating information about CTCs among patients in the CARD trial and thinking about responses at GU ASCO 2021. Can you tell us a little bit about that?

Eleni Efstathiou: Thank you for this opportunity, and really, the CARD trial is a trial that succeeded against a lot, because there wasn't a lot of excitement at first and accruing. As we have discussed previously, physicians were like, most of us in the academia never really wanted to sequence androgen-signal inhibitors, but we had to prove our point and that has been proven. It's a New England paper. But then, the trial becomes a trial that keeps giving, and that was the reason why I participated from the translational biomarker standpoint.

Now, if we take a little bit of a step back, we should all agree that the circulating tumor cell story, starting a while back, is something that, it's been exciting academically, there's been a lot of beautiful papers. Very consistent. People like Johann de Bono, Howard Scher, have worked for years on all the platforms to prove these points, but it has not caught on, even though we do have one platform available in some centers. For multiple reasons.

I want to point out that in the case of the CARD study, the one that was used was the Epic Biosciences platform, which I find very fascinating, because it reminds you a little bit of a transition from a tissue to a liquid biopsy. Because what you do is you put those circulating tumor cells, essentially, on the slide. It's like a good old school psychology. And then you've got the ability, not just to count them, but to also assess them with molecular characteristics. And that's going to be a big part of what we're hoping to give out moving forward. So we already had some very nice data from the past, from this platform, suggesting that a conversion to 0, if you can detect them with baseline with any of the treatments available, is the best bet for good solid response and overall survival benefit. Howard Scher was extremely convincing presenting that.

So, we took that, and it was a predefined analysis, this is not a post-hoc, which becomes super important as well. So it's not just a fishing expedition, is what I'm trying to say. We collected samples at baseline screening, and at least cycle two, and if we could, and we could in a lot of cases, at the end of treatment. This time, we presented the changes from baseline to cycle two, which is an early event, it's just after one cycle, essentially, of treatment and also the association of baseline with outcomes.

Let's start with the association of baseline with outcomes. Obviously, detectable and high CTC count as a continuous variable associated with a poor outcome in general. When you've got detectable CTCs, we know to tell our patients, "Okay, we've got a big fight ahead of us. This is not a good start." But what becomes important is to look at the conversions again, and we see clearly that a conversion that happens even after one cycle, from a detectable to an undetectable, or even to a lower, is a very favorable readout, and associates wonderfully well with overall survival. Even though it does associate with other biomarkers, such as LDH, PSA, it stands out also, though, as independent in the multivariate analysis. And that becomes important.

But the new thing that we also looked at, is specifically at those circulating tumor cells that are high cytokeratin-expressing, and the clearance of those CTCs was double in the active arm, which was cabazitaxel, versus the enhanced androgen-signaling inhibition, which also becomes important. It points to the fact that we need to look at specific CTCs. So hopefully ASCO, or another meeting, ESMO, we're going to be reporting more on specific biomarkers within those CTCs.

Alicia Morgans: That's really fascinating and so important, and as you said, I think it's interesting that it's the Epic Biosciences platform. I think I've heard them describe it as 'no cell left behind'. They truly are able to evaluate the morphology, they're able to really, obviously, count the cells. But to dig more deeply, I'd love to hear your thoughts on what do you think is happening with these cytokeratin-positive cells? You mentioned that these may be the ones that we need to watch for. What do you think the biology is there?

Eleni Efstathiou: It's been something that I've looked back in the literature for the past 10 years, several investigators have been looking at high cytokeratin across solid tumors, and the data is very conflicting. What I can tell you is that what we need to look at, and it could be an epiphenomenon that's more speaking to multiple genomic events within those specific cells. We don't know. We have to look at it more carefully, because if you look at older studies with different technologies, and as we know, assay is very, very important, they do not really speak to our finding. Which again, I say, it's a predetermined perspective, we can call it ambispective because we went back and looked at results. It's the first of its kind, so a lot more to come.

And I think, again, if somebody is really interested, I would recommend, go look at the poster, go listen to Johann, present it and speaks to that, 'no cell left behind'. And remember, the good thing about this platform is you can store those slides in your freezer, and when the time comes or you've got a new biomarker, go check them, exactly like you do with paraffin-embedded formalin-fixed tissue.
So with that in mind, I wanted to bring up another point that's close to what we were saying about new, interesting things. Remember, we were talking earlier about the importance of sequencing of treatments before we started this discussion, and essentially, for years, all of us have been fighting to get enhanced androgen-signal inhibition early, early, early on. Now, if you look at the table of the results here, you'll see that interestingly, tumors that had been treated first with docetaxel and then with an enhanced androgen-signal inhibitor, actually had a higher percentage of circulating tumor cells detectable. 62% of the tumors had detectable CTCs. Whereas if you have tumors that had first been targeted with abiraterone and enzalutamide then with docetaxel, only 30% of these tumors had CTCs.

Does that speak also to the biology and the need to have the right sequence to avoid further events of resistance? I would say, yes, it has to be proven in a similar fashion like what we're seeing with high of cytokeratin.

Alicia Morgans: Again, that is fascinating, and thank you for your point about the way that we can store these slides and come back later, because I do think this is something that you and the team are really, of course, whetting our appetite, because now, hopefully we'll be able to go back, do some multi-variable models looking at cytokeratin and the sequence of therapy. You may be able to provide even more insights over time as we continue to struggle to sort out what the best sequence is, which may vary on some clinical characteristics or some patients characteristics, but may also be informed by CTCs and other molecular markers that we are still developing.

So, I love that you're able to continue to analyze the CARD data in this way, and hopefully inform more than just a single treatment period in time, but perhaps the sequence of treatments that patients have received preceding the addition of cabazitaxel. It's really fascinating. As you think about just sort of summarizing this particular analysis, your findings and where they actually fit in the treatment landscape, what would you say?

Eleni Efstathiou: I would say that, first of all, this clinical experiment actually confirms the efforts that started years ago by people like Howard Scher. He was the first to work with them and to be very enthusiastic, and we have to give that to him. He was fully dedicated to it. And being linear and committed pays off, even though it's so hard. So we're cashing in now and we're seeing that, actually, if you used such a liquid form of biopsy, you might be able, beyond just prognosticating it if your patient is in trouble, you might be able to, early on, tell the patient, where you can't tell the PSA, that, "We're good. You're responding." Remember, 30% of patients who are treated with taxane will have this flare phenomenon. You can't tell, you just need to keep on going.

And inversely, within this trial, we saw that also those who had a rise in their circulating tumor cell count early on, they did not perform well. So we can put you on the alert to monitor that patient more carefully. We might be able to bring on having a good biomarker to trace when PSA is not helpful, the responsiveness and the early responsiveness of treatment. Furthermore, as you suggested, clearly, this is the opportunity to use CTCs to actually characterize a tumor and sequence accordingly.

Alicia Morgans: I think that's fascinating, and I so appreciate your insights. As we continue to do work in prostate cancer, I think we continue to recognize that cancers and the people in whom they dwell are all biologic systems. We just keep peeling back these layers of biology, and hopefully, at one point, we'll be able to read the book more clearly. So, thank you so much for your time, for your efforts, for your explanations. We really, really appreciate you.

Eleni Efstathiou: Thank you. Thank you for having me. Always a pleasure.