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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm excited to have here with me today a good friend and colleague, Dr. Michael Morris, who is the Prostate Cancer Section Head and a GU Medical Oncologist at Memorial Sloan Kettering in New York, New York. Thank you so much for being here with us today, Dr. Morris.

Michael Morris: Thanks so much for having me, Alicia. It's a pleasure to be here.

Alicia Morgans: Always a pleasure to talk to you, and we have so much to talk about this year. At this point, I'd love to talk with you about some updates on the CONDOR trial that your team presented at ASCO 2021. Remind us, what was the CONDOR trial and why were you doing this work?

Michael Morris: So, just as a reminder, the CONDOR trial was one of two studies that supported the FDA submission and subsequent approval of DCFPyL, which is an F18 radiolabeled PSMA directed PET tracer. And CONDOR was the study that focused specifically on the rising, the biochemically relapsed patient population, those who had surgery or radiation as their definitive primary therapy, biochemically relapsed, and then per their local institution's standard workup and evaluation, had negative imaging. And this study was essentially getting a PyL scan and then getting a series of additional studies to verify whether or not that PyL scan identified the actual disease in the scan's positive lesions. So that composite was comprised of either histology or correlative imaging with additional imaging focused on the area that was positive on the PyL scan or radiation-induced PSA changes if they got radiation to the site. And then there was a questionnaire before and after the scan as to whether the treatment had changed by virtue of the scan in the clinician's opinion. That was basically the study.

Alicia Morgans: I think when you and the team reported the results previously, it was pretty clear that this DCFPyL radioligand tracer really did an excellent job of identifying what was prostate cancer, metastatic disease.  It really did not have a high false-negative rate. It didn't have a high false-positive rate. And the localization seemed to be consistent across different folks who are reviewing the imaging. Was that the case?

Michael Morris: Yeah, the primary endpoint was something that was called the CLR, the correct localization rate. It was really focused on the positives of the scans. So it was, CLR is really another way of saying positive predictive value, but not just positive predictive value, but with additional co-localization from the scan to determining ultimately what the positivity was. So it's a positive predictive value with the localization of the lesion as well. And so if you looked at the three independent readers whose reads were then matched with an independent standard of truth committee, if you will, looking at this composite determinant as to whether a positive was a true positive, there was really good agreement that between the standard of truth and between the scan finding. And so that CLR rate was around 85% by each of the three independent readers. So yes, if you saw a positive on the scan, it was really quite likely that that was indeed disease as measured by this composite standard of truth.

Alicia Morgans: And I think that's so important as we think about this tracer being available more broadly as it has been FDA approved at this point, and hopefully will be available to all of us within a relatively short period of time. And the update that you and the team provided at ASCO 2021 really helped to clarify whether this composite endpoint was being driven by one aspect or another, or whether all of these aspects of your composite endpoint were actually on the up and up, were actually positive. And what did you find?

Michael Morris: So this was a nice poster that was presented by Frederic Pouliot who is from the University of Quebec representing the CONDOR team. And what he did was he analyzed not just the composite endpoint that had been used as the determinant of truth, so to speak, in this study but also broke each element of the composite down. So you could see if perhaps there was one specific element of the composite of truth that was perhaps driving the excellent CLR rate, which was 85%, to see whether one might have been better than another, or that one was, you know, could be replaced by another, or et cetera, or whether it was just consistent overall elements of the composite.

So just to remind everyone that composite was determined by either, and then this was hierarchical histology if it could be obtained, but of course, most of these patients did not have really a biopsy of old material because by definition they didn't have visualized disease by their standard imaging or by composite imaging which could have been CT, MRI, bone scintigraphy, or fluciclovine, or by this PSA change if they had their lesion irradiated and if the PSA declined by 50% after that.

So most of the patients had correlative imaging. There were some patients who had in fact histology. It was about 35 of the patients who had histology or excuse me, 31 of the patients who had histology. A hundred of the patients had correlative imaging and only one patient had post-treatment PSA data. So the histology was then compared to the correlative imaging because that was most of the patients. And what Frederick pointed out was, and demonstrated, was that the CLR rate, the primary endpoint, upheld regardless of whether it was a histologically proven true positive or imaging proven true positive and within imaging, whether that was fluciclovine or whether that was MRI or whether that was CT. They all held up, basically.

And that was regardless of the PSA value that the patient was imaged at. So he categorized them in the traditional groupings of less than 0.5 or 0.5 to 1, or 1 to 2, et cetera. So in other words, it was pretty uniform across the composite endpoint of its component pieces of that composite and the diagnostic capacity of PyL held up regardless of the modality that was used to verify whether the lesion was a true positive or not.

Alicia Morgans: Well, I think from a clinical perspective, that is highly reassuring because, you know, if we did see a signal that it was really only correlating with one aspect or another of that correct localization rate, we would be maybe concerned that maybe that true positive is not what we expect it to be. That we will have lesions that are not actually prostate cancer. So from your perspective, how do you interpret these findings in your clinical practice? And as you have access more regularly off trial to the agent, how will this potentially affect what you do in the clinic?

Michael Morris: So I think that is a great question because I think the biggest question that, you know, that the study generates in terms of the actual practical application of PyL and deploying PyL now that it's commercially available, is do you need to do all of that work to verify that a lesion is a true positive? If you see it, what is the level of confidence that you can believe it? And do you need to do additional imaging or a biopsy in order to verify what you see? And I think that the answer is no, that when you see a positive, it's really quite likely that that positive is positive. So you don't necessarily need to do any of that additional work in order to establish that you have the confidence that it is a real lesion. This doesn't mean that there might not be other reasons not to do it, you know, to do those other assessments.

So for example, if you saw a lesion on a PyL scan and you wanted to do a biopsy in order to secure material to genomically profile, well, that's fine. But what you don't need to do is to do that biopsy in order to verify the reliability of the PyL finding. That is, you can trust the finding within the parameters that we've described, the CLR rate being 85%. So I think that what CONDOR showed us is that you do not need to do those things in order to have confidence that a true positive exists when you see a lesion.

Alicia Morgans: I agree. It doesn't necessarily tell you what to do when you know that there is a disease that has spread. That you still have to think about and talk with your patient and, you know, refer back to try to understand how to best proceed. But at least you know you can trust your eyes, which I think is really important as we are moving into a new era of more sensitive imaging that has raised questions over time about how trustworthy this imaging modality will be. And it's also nice to know that this held up over three independent readers, which of course provides more reassurance that hopefully in our institutions, as our nuclear medicine folks or the radiologists are becoming more familiar with these modalities, they will be able to tell us what they see, and we can all trust what they say. 

Michael Morris: If you look back at the label of the first molecular imaging studies approved in the U.S. like choline, the label indicates that you should, if possible, get a biopsy to verify what you see. And that's not true of the PSMA imaging labels, because there is just more robust evidence by virtue of the designs of these prospective studies that when you see a positive, it's quite likely that it is a true positive. And it saves the clinician and the patient that additional work, that you have more confidence in the diagnostic ability of these agents, both the gallium and the PyL, that subsequent testing is probably not necessary.

Alicia Morgans: Great. So thank you for sharing this. Thank you for this update. Final words. What is your message to listeners on the CONDOR study and this updated information?

Michael Morris: I think that the most important thing is now how to best use these as opposed to diagnostic performance. Now that we do have by virtue of both OSPREY and CONDOR, a commercially available, nationally approved PSMA PET, there are a few issues. First, getting it to patients and clinicians. Second, the reimbursement issues. And then third, the appropriateness of use. And all three of those of course are works in progress. But what is so nice to see now is that it is rolling out across the country. There is increasing availability and the reimbursement issues will look like they are going to, you know, firm up in terms of some decisions in the early part of the next year. And it's a good problem to have, to have a test that is now available to figure out its best use and applicability.

Alicia Morgans: Well, always more work to be done, but at least as you said, we can believe our eyes, that the diagnostic information that we are getting seems to be credible, seems to be able to more sensitively detect what we are looking for, which is a metastatic disease from prostate cancer. I really appreciate your conversation today and interpreting this. We always appreciate your expertise. Thank you, Dr. Morris.

Michael Morris: Thank you so much. It's always a pleasure to be here on UroToday.