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Zachary Klaassen: Hi, I'm Zach Klaassen, a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined on UroToday by Nuclear Medicine Physician Phil Koo at Banner MD Anderson in Arizona. Phil, thanks very much for joining us today.

Phillip Koo: Yeah, a pleasure to be here. Thanks for having me.

Zachary Klaassen: So, Phil, we're going to talk about the COBRA data, which came out at ASCO, and we've had a previous conversation with UroToday about the new 64-copper PSMA PET imaging. Just by way of background for our listeners, can you take us through the design of this molecule and some of the early COBRA data that was presented at ASCO?

Phillip Koo: Sure, happy to. The compound is copper 64-based, what they call SAR-bisPSMA. I think what makes it a little unique compared to some of the other PSMA diagnostic agents that we've seen is that this molecule actually has two binding motifs. So if you look at this cartoon, you see that the PSMA molecule that targets PSMA is able to attach not just at one receptor but at two receptors simultaneously. Hypothetically or theoretically, the ability to stick and stay attached to the prostate cancer cell would be greater with something like this. What's also unique about this compound is the chelator itself, which helps protect the isotope. It's almost what they describe as a sort of cage type of technology, which makes sense as well. So, I think for those two reasons, maybe this might be able to increase the signal-to-noise ratio that we might get when we target the PSMA receptor.

So this molecule was studied under the trial called COBRA. It was a phase 1-2 trial that looked at a standard dose of copper 64 bisPSMA in patients who were eligible for this. This study looked at patients who had suspected recurrence of prostate cancer, either based on a rising PSA or detectable PSA. You obtain a PET-CT scan after the injection of the molecule at either one to four hours, and that was labeled as day zero. What was unique about this trial is that they were able to bring patients back the next day as well. So at 24 hours plus or minus six hours, they re-imaged these patients just to see the effects of what this delayed imaging might create with regard to performance. Then, obviously, these patients were followed continuously as well. You know, we talk a lot about the results, and Dr. Shore goes over the trial results in the prior video.

But just to summarize some of the top-line data from this that I think is interesting is the fact that the number of lesions identified on that next-day image, as opposed to the day zero image, increased by 82%. So what you're seeing is maybe that molecule having more time to circulate, attach, and stay attached to the prostate cancer cells. Because of that, you're seeing this significant increase in the number of lesions detected, and the number of patients actually having a positive scan went up 34%. So these are patients who might have been negative on day zero and all of a sudden positive on day one, which to me is even more meaningful than just having more lesions detected. For these reasons, there's a lot of excitement about what this might mean for all of us diagnosing and treating prostate cancer.

Zachary Klaassen: Thanks so much for that overview, Phil. That was great. I think for our listeners, tell us a little bit more about this molecule and what the flexibility is regarding half-life, and how scheduling may be able to be a little more flexible, maybe for access in terms of areas that don't have PSMA PET because they're outside of distribution regions.

Phillip Koo: So we talked about the molecule being bivalent and having that cage technology. I think what also makes this molecule unique is the fact that it's using a copper 64 isotope as opposed to a gallium 68 or fluorine-based isotope. The main difference is the half-life of copper 64 is just under 13 hours. For reference, a fluorine molecule's half-life is around two hours. That longer half-life allows it to have a longer shelf life. From a commercial perspective, it's possible to have one, maybe two, manufacturing facilities and then ship this across the country or across the globe to sites using FedEx or companies such as that. Once it arrives, your shelf life is longer, so you could actually use that dose with more flexibility. I think those are some advantages that this provides, as opposed to needing a gallium 68 generator nearby or needing a cyclotron nearby to make the isotope that attaches to the molecule.

Zachary Klaassen: That's great. Maybe walk us through how you would talk about this with patients. If somebody identifies with biochemical recurrence, and you think they're going to benefit from a copper PSMA PET scan, how do you tell them they're going to get injected on day zero? We may or may not scan you that same day, but we're definitely going to scan you the next day because of these results we just talked about. How would that look in the clinic in terms of counseling?

Phillip Koo: If this data is similar in a larger phase 3 trial and you're seeing that better performance on that next-day imaging, I think it's a very interesting discussion that we can have with patients. If the results of that next-day imaging are really compelling, then that will likely be what we are going to try to do in terms of our protocol. We'll have patients come in, get injected, go back home or wherever it might be, and then come back the next day to get images on a PET scan. Some patients are going to be coming from further distances where maybe staying the night or coming back again might be logistically challenging. In those cases, maybe we say, "Hey, we're just going to do same-day imaging and we might forego the next-day imaging." In the end, it's going to really come down to the performance and the specific clinical scenario with regards to what pathway we choose. But again, I think it opens up a lot of different possibilities. If that performance is better, I think it's wonderful for the physicians and the patients.

Zachary Klaassen: Absolutely. So maybe from your position as a nuclear medicine physician, tell us a little bit about the day zero to day one, SUVmean/max, and some of that tumor-to-background ratio that you're seeing on these scans?

Phillip Koo: What I think we're going to see is an increase in the amount of radioisotope, radiopharmaceutical that it's concentrating. So, what you anticipate is that the SUVmean, SUVmax, all those semi-quantitative parameters will be higher with this type of copper compound as opposed to some of the other compounds we've seen. What does that mean? I don't think we know yet. I think at a minimum, the fact that the quantitative values will be higher is that they should be more visible and detectable by PET. But I think down the road, when we start thinking about how we use those quantitative values to see how we manage patients, I think it's really to be determined, but it's exciting. I think something like this that can improve performance is something that we should be excited about and need to explore.

One other comment that I neglected to make is from an operational standpoint, being able to inject patients and have them leave is actually a good thing. So patients can come in for a quick visit, get injected, and then go about their day. The next day they come back, they could go straight onto the PET/CT camera, get imaged, and then go home. So, the total amount of time spent in the hospital could potentially be less for those patients than with some other agents. And from a hospital or imaging center perspective, we could probably increase our throughput because we don't need patients to wait in the facility as the radiotracer distributes throughout the body.

Zachary Klaassen: I could see too where situations arise where somebody comes in, they're coming from out of town, they're supposed to get in at 8:00 for an injection, but they get in at noon. They stay the night, they're supposed to come in at 8:00, but they decide they want to sleep in and come in at 10:00. No big deal, we're all within the window?

Phillip Koo: Yeah, no big deal. Get injected, go shop, go play golf. Do whatever you need to do, come back at a specified time. If you're late, not a big deal. We could figure it out.

Zachary Klaassen: So, from a higher-level clinical view, we're detecting more lesions, we're detecting smaller lesions as small as two millimeters in the trial. How do you see this in terms of how we sit down with the patient after this invasion, and how we treat their biochemical recurrence? What's the clinical impact?

Phillip Koo: I think when we talk about biochemical recurrence, the space where we hope something like this can have the biggest impact is in patients with oligometastatic disease where we're thinking about METS-directed therapy. There might be a possibility of curing these patients who have these low-volume recurrences. In that setting, I think it's vitally important that we can detect as many of these lesions as possible. If that's the case, then yeah, if we could zap them or take them out via surgery, maybe we are going to give them a chance of cure or maybe a durable response. Looking at something like this in patients pre-definitive therapy, I think it's a little different. We know based on a lot of other trials, our sensitivity of PSMA PET in that setting is relatively low, in the 40-45% range. To be able to detect all of the microscopic disease in all those lymph nodes may be a bar that we will never be able to achieve, but maybe there's an opportunity with better performance to be able to have some improvement in response to our therapies at that stage.

Zachary Klaassen: Absolutely. So let's look out over the next, say, two to five years: phase 3 trials, both in the biochemical recurrence setting as well as in the high-risk staging. What's up next for the copper PSMA PET scan?

Phillip Koo: Now that they have the phase 1-2 data released, they're starting a phase 3 trial, which will hopefully lead to an approval in that BCR space. They have a trial ongoing for patients pre-prostatectomy so that the results for that phase 2 trial will hopefully lead to a label in that disease state as well. I think in the end, it's exciting to have so many different diagnostic PSMA agents available, and this is where in the past we've sort of commoditized it. We say, "Oh, you could just use one or another." And for the time being, that's probably true. But having multiple different molecules with different chemical structures and different performance values, I think, gives us an opportunity to be much more sophisticated with how we approach the use of diagnostics and how we pair the diagnostics with therapeutics as well. So the more the merrier, and I think this is just a great step forward for all of us in that prostate cancer space.

Zachary Klaassen: Absolutely. Great discussion as always, Phil. Maybe a couple of take-home messages for our listeners.

Phillip Koo: I think there's always a tendency to want to make things simple, which we want to do. But something like this, where it's new and has new potentials, are things that we should get excited about and explore. If we're able to prove performance, let's figure out what this means for our patients. We should design trials that pair diagnostic agents with our therapeutic interventions so that we can truly figure out which diagnostic agents to use and which maximize those clinical outcomes. So the take-home message is, the PSMA space isn't getting dull, it's getting more exciting. So stay tuned, and hopefully we can keep this momentum moving forward.

Zachary Klaassen: Absolutely. Thanks again so much for your time and expertise, Phillip. Really appreciate it.

Phillip Koo: My pleasure. Thanks, Zach.