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Phillip Koo: Hi, my name is Phillip Koo. Welcome to UroToday. We're very fortunate to have with us Dr. Neal Shore, who's the medical director at the Carolina Urologic Research Center, who's very familiar to us given all of his groundbreaking work in so many different parts of the whole prostate cancer spectrum. So thank you very much, Neal, for joining us.

Neal Shore: My absolute pleasure. Great to be with you, Phil.

Phillip Koo: So today we're talking about, we're sort of continuing the discussion about these copper 64 PSMA compounds and there's this new product from Clarity about to be studied in a larger phase three trial. But before we get into that, could you explain to us some of the benefits or unique aspects of this copper 64 PSMA diagnostic agent?

Neal Shore: Yeah, absolutely, Phil. Look, now the PSMA PET world has just dramatically exploded. A lot of great scans that are already approved and the basis of that new improved diagnostics has opened up the world of what we call now theranostics or radioligand therapy. I think it's great. We already have three different approvals and various on-the-market PSMA PETs. And as you said, the copper moiety is being studied by Clarity and other companies as well. So, happy to go over the trial landscape in Clarity today.

Phillip Koo: Before we get into the details about this phase three trial, talk to us a little bit about how this compound is different from some of the already FDA-approved PSMA products.

Neal Shore: I think that's really important. We'll probably see it in the next slide, which is the molecular basis for this. So that's the background and that's an important question that you're asking. I think it's important to recognize that whether you're using gallium or 18F, these are really great molecules that identify PSMA avid sites. And as everyone who's been using this recognizes, it's a little bit of a misnomer because prostate-specific membrane antigen could be on other areas besides prostate cancer and normal prostate. It can be in the parotid and salivary glands. It can be in the kidneys and in GI vascularity. But what you see here, Phil, is that this cu-SAR-bisPSMA, why is it unique? It's this bivalent structure and so you're really having two specific areas on the actual antibody that can bind, and with this very unique chelator, which sort of binds the two copper moieties together, it allows it to really find the PSMA so you really have two areas of stickiness as opposed to one.

I think the other thing that's kind of key about it is the half-life. This particular copper 64 half-life is a little over 12 hours. Gallium and 18F are less than two hours. So why does that matter? Well, number one, this cu-SAR-bisPSMA as it's described, plus the longer half-life, potentially could have a higher uptake where you see PSMA expressed because of this kind of bivalent moiety. And then the other thing is the much longer half-life, which is really kind of fascinating, is that it gives you the ability to inject patients and you can scan them on the same day, but as we all know everyone's super busy with scheduling and throughput, and you now have the ability because of this much longer half-life to image the patients same day but also next day.

And what some of the earlier studies have found is that when we look at these patients, we're seeing more detection or greater detection on the next day compared to the same day. And we've actually had some data, it's early, small numbers, but detecting lesions as little as two millimeters.

Phillip Koo: So this idea of next-day imaging is new when it comes to prostate cancer imaging using these PET agents. There was that trial, the COBRA trial, which you talked about earlier, you presented that. Just what are some of the top-level results with regards to performance and this idea of next-day imaging?

Neal Shore: We're starting to see, at least from COBRA and PROPELLER, two earlier phase studies, one in BCR, another one in pre-prostatectomy high-risk patients, what we're seeing is that by the second day we're getting greater detection levels, and those were essentially confirmed with what we've historically started to call this standard of truth... getting tissue material itself to confirm or seeing a change in the imaging after instituting an antineoplastic regimen, typically testosterone suppression or subsequently seeing confirmation radiographically with another imaging modality, CT scan or MRI... these sort of concepts of what are referred to as standards of truth.

So based upon that, the copper-SAR-bisPSMA, it's a long-sounding expression... I'm sure we'll come up with a better name or a more concise commercial name if and when it gets approved... but what you're seeing because of this bivalent structure, greater ability to find PSMA because of the moiety, the longer half-life, I think it's going to give a lot of flexibility in clinics where timing becomes really important. So you can inject a whole bunch of folks on the same day and send them home and then bring them back the next day, and so get a lot greater throughput.

I think this throughput issue, what we're seeing now for our colleagues who are using gallium or 18F PSMA, because of the half-life concerns, the transportation of the moieties, scheduling of patients, I think this is going to really... not maybe for all centers but for some centers, and frankly I think very busy imaging centers in the community that may not have multiple cameras but may only have one camera... I think this is going to be something that could be very advantageous from a practical standpoint.

Phillip Koo: Yeah, I agree. I think there's some flexibilities that this creates that allows for more efficient use, more efficient timing of when the patient gets injected and when they get imaged. So it's very exciting to see this phase three trial now come about. It's called CLARIFY from Clarity Pharmaceuticals. Can you tell us more about some of the details of this trial in this hybrid setting?

Neal Shore: Yeah, thanks. I mean you see the slide up here. This is the study design. We're actively accruing and almost 400 patients. Essentially you're going to look for patients who have histologically confirmed prostate cancer that haven't been treated. They're high risk. So we're looking for patients who are going to go to prostatectomy and you can see the stage T3a or greater and they have to be grade group four or higher or a PSA of greater than 20, and they're all going to undergo radical prostatectomy with fairly extensive pelvic lymph node dissections. They'll get screened. They'll get studied and they'll get a same day as well as a next day. That's the thing that's pretty unique about this.

So it'll provide that clear flexibility. We'll have the results. We'll get the very, very methodologically described within the sites the importance of the pelvic node dissection, and that's sort of your ultimate standard of truth getting tissue. So that's the study. We're actively enrolling patients. The objectives, primary objectives, the diagnostic performance both same day and next day, and you may want to call that day one, day two. We'll be looking at the co-primaries of sensitivity and specificity based upon this standard of truth. It'll be a blinded, independent, central reviewers. And then of course the usual other important secondary endpoints that you see outlined.

Phillip Koo: Let's talk a little bit about the impact that you foresee for a tool like this. And we know from the other trials looking at PSMA diagnostic agents that the sensitivity in this space before a definitive treatment, before radical prostatectomy, is usually in that 40 to 45% range, but specificity is very, very high in that 95, 98% range. Can you tell us about how potentially this with next-day imaging might impact the clinical care of these patients before an RP?

Neal Shore: Yeah, I mean that's a great question. And I think that if indeed we can show greater sensitivity, as you say in the other studies it's in that 40 to 50% range, but as you'd expect because of that really kind of rigid standard of truth, it's good to see that the specificity is very high. I expect it to be equally as high, but we're kind of hoping that the sensitivity is going to be even higher for these patients because of that day two next-day evaluation. And much like other important regulatory approval trials that led to gallium and 18F approvals that we have, we'll be following very similar pathways for that standard of truth.

You do the studies, I'm certainly cautiously optimistic that we'll be able to show that. It's exciting and it's great for the patients, right? Because if you can show that indeed you have a test that may be able to give you an enhanced sensitivity, we still pretty much... despite the current approved PSMA PETs... at least when we ask this question do you still do a pelvic node dissection, the answer is absolutely yes. That seems to be the consensus when we have those conferences. But of course, we're always trying to get more information to better inform our patients. Should we proceed to surgery? Should we proceed to radiation? If we're going to proceed to radiation of the prostate would we also include the pelvis or not? And so I think these are going to be some of the ongoing questions and discussions for us to continue to debate.

Phillip Koo: Well, that's wonderful. I think we're all very excited about this as well, to be able to have a tool that is more accurate and can improve sensitivity. And even with negative studies, being able to say with greater confidence that a negative study is truly negative, I think, is powerful. So we're very excited about this and appreciate you leading this charge as well. So we look forward to hearing the results, hopefully, once this is all enrolled. So thank you very much for joining us.

Neal Shore: Thank you, Phil.