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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Dr. Louise Emmett, who is a nuclear medicine physician at St. Vincent's Hospital in Sydney, Australia. Louise, thanks very much for joining us today.

Louise Emmett: My pleasure. Thanks for asking.

Zach Klaassen: We're going to talk about some exciting data surrounding the copper PSMA agent in CLARIFY, which is a phase 3 trial. Before we get into that, I'd love for you to walk us through what makes the copper agent different from some of the other agents we're familiar with and what's the uniqueness of this structure?

Louise Emmett: Yeah, okay. So first of all, what we've been using up till now are fluorine-labeled PSMA PET agents and gallium PSMA PET agents. These agents are super good, target the PSMA receptor very well, and we've got a lot of information on how accurate they are and how effective they are in changing management in prostate cancer, particularly in staging and biochemical recurrence. How is the copper different? Gallium has a one-hour half-life, fluorine has a two-hour half-life, and copper has a 12-hour half-life. So first of all, the imaging characteristics between fluorine and copper are very similar, but the fact that it's got a 12-hour half-life means that you don't have potentially so many problems with bladder activity. You can wait a long time before you image and still get very, very good images once we've completely cleared out the bladder. So we get a really good image of the prostate potentially without too much bladder activity or the prostate fossa. We know from previous studies that PSMA as a receptor, if you target that with gallium PSMA or fluorine PSMA, you get incremental increases over time in intensity and metastatic deposits.

So this long half-life is a little bit of a game-changer in terms of being able to follow patients for longer and have potentially a higher sensitivity than you would with either gallium or fluorine. That's the thing that really needs to be determined. The second bit of this agent is that it's not just a single peptide that's targeting the PSMA receptor, it's a bifid peptide. So it's two peptides, and you can see that really, it's got a cage that's been built or a chemical cage that's been built around the copper. At each end of that chemical cage, you have a PSMA peptide that can then bind to the receptor. So technically, you should get twice the binding that you would get with a single peptide if you're injecting, because it's easier for it to bind. In my studies with copper-64 bisPSMA, so this peptide, we've actually found that. So you get incredibly high binding to the receptor itself. That means that technically, you would get really good uptake in the cell with this. The target is very bright compared to a single peptide agent. So there are two reasons why it's got potential.

Zach Klaassen: Excellent, excellent. So before we get into the trial design of CLARIFY, take us through some of the earlier trials, looking at this indication for staging of high-risk prostate cancer.

Louise Emmett: Yeah. So the first trial in the copper-64 bisPSMA agent for imaging of prostate cancer was done in patients who were going for radical prostatectomy and who'd also had a gallium PSMA-11 study. They were looking to see safety and efficacy in this phase 1 study. It was also a dose-finding study, so they had a couple of doses, and they also did multi-time point imaging to try and work out what dose should be injected, whether it was safe, were there any safety concerns, and also how it really compared at a preliminary level to gallium PSMA-11 in these patients being staged prior to radical prostatectomy with prostate cancer. So as I discussed with the copper and the bifid nature of this agent, it does definitely look like the intensity of the copper-64 agent is brighter than gallium PSMA-11 for each lesion identified. So this is a case where there's a very small node directly adjacent to the bladder. It's quite hard when you have metastatic disease that is adjacent to the bladder because of the intensity of the bladder on most imaging agents with PSMA.

This is gallium PSMA-11 that you can see on the top. These images were done within two weeks of each other. So on the gallium PSMA image, this node had an SUVmax of four, so not particularly bright, and was actually missed by... The central region was also missed by the local reader. It was not called. But if you look on the image underneath with the copper-64 bisPSMA, there's less bladder activity getting in the way. The bladder itself is much less bright than the gallium PSMA-11 study, and the node is showing up very brightly. That's because the SUVmax is 18 on that node compared to four on gallium PSMA-11. That's very helpful for the readers in terms of being able to identify small lesions.

Zach Klaassen: Excellent. Beautiful images. There's one more slide on PROPELLER. Maybe just walk us through this one as well, please?

Louise Emmett: Yeah, I mean, I think that the phase 1 study with PROPELLER, it really wanted to have a look to see how much activity there was at known sites of histopathologically positive adenocarcinoma of the prostate. So what they did was they did this pre-radical prostatectomy and then compared it to the radical prostatectomy specimens. What you can see here is comparing the gallium PSMA-11 on the left. So the PSMA-11 is definitely positive. It's not abnormal. It identified both sides of disease in these patients, but it's much clearer on the copper-64 bisPSMA with an intensity that was more than twice as bright as the gallium PSMA-11. That's actually quite interesting because it's a bifid, so you'd expect it to be twice, but somehow in PROPELLER, it seemed to be a little bit brighter than just double.

Zach Klaassen: Right.

Louise Emmett: So that, I don't know what that bifid technology is doing with the two PSMA peptides, whether it's going into the cell and perhaps getting stuck for longer, or whether it's because you can do more delayed imaging, it has more time to get into the cell and stay in the cell. Whatever it's doing, it seems to be concentrating very nicely in the cancer.

Zach Klaassen: Absolutely. So that's a great background leading up to this slide, talking about the study design for CLARIFY. Maybe walk our listeners through the patients that are being included and what the trial looks like.

Louise Emmett: Yeah, so this CLARIFY trial is very similar to the other registration trials that have been done for fluorine-18 DCFPyL and also for gallium PSMA-11 in patients being staged with prostate cancer prior to radical prostatectomy. It's for patients with confirmed adenocarcinoma of the prostate who have high-risk disease, such that they're going to be going for pelvic lymph node dissection to evaluate the lymph nodes. The study is looking at the primary endpoint of sensitivity, specificity, and accuracy of copper-64 bisPSMA PET-CT to detect metastatic disease, particularly within the nodes.

Zach Klaassen: Excellent. You led into that perfectly. So the primary objective is to assess the performance, and then we have the primary endpoints. Maybe just walk us through some of those secondary objectives and endpoints as well.

Louise Emmett: Once again, this is a registration trial, so the diagnostic performance is the primary endpoint, but the study's also looking to evaluate safety, positive and negative predictive value, and also get a lot of information on the dosimetry and pharmacokinetics of this really novel new imaging agent targeting PSMA. I think that's very important for us to understand very clearly exactly what's happening with this. The trial's aiming to get a lot of information about how long it hangs around, where it goes, when the imaging should be done, whether the one to four-hour time point is better or worse than the 24-hour time point, exactly how we should manage our patients with this new agent.

Zach Klaassen: Absolutely. There's a very important point at the bottom talking about being open for recruitment. Maybe you can give us an update on where the trial stands currently.

Louise Emmett: So I think the trial is currently open at about nine centers in the US. It's open at two centers or nearly open at two centers in Australia, which is super exciting for us in Australia because people don't often bring phase 3 trials to Australia.

Zach Klaassen: Yeah.

Zach Klaassen: Absolutely. So let's be a little bit provocative because that's the beauty of doing these discussions. So let's fast-forward. Those 383 are done, we're reporting results. Let's assume this is a positive trial for CLARIFY. How do you see the copper PSMA agent fitting into the landscape given that we have DCFPyL, we have gallium.

Louise Emmett: Yeah, it's a busy space, right?

Zach Klaassen: Busy space. So how do you see that working into which patients would be important? How would you utilize it?

Louise Emmett: How would I utilize it? So I think at the moment, in the studies that have been published to date, the sensitivity of PSMA PET agents sits between 25% and 50% in the published literature. Specificity is excellent...

Zach Klaassen: Yeah.

Louise Emmett: ... but 25% to 50%, and the reason for that is because you can see with that gallium PSMA-11, it's not particularly bright, and it's not particularly bright with low-volume disease. Unfortunately, cancer doesn't guarantee to be a particular size. So when you look at the median node size in prostate cancer, it's sub five millimeters, and that's a real struggle for PET cameras. So I think that if they are able to show a good sensitivity with this new agent and maintain specificity, then that's really important...

Zach Klaassen: Yeah.

Louise Emmett: ... in the staging space. Then I'm particularly keen in the biochemical recurrence space on finding agents that are more sensitive.

Zach Klaassen: Yeah.

Louise Emmett: We know that about half the patients who are imaged with biochemical recurrence, who have a PSA that is still low enough for them to be curable with salvage fossa radiotherapy, will have a negative PSMA PET scan.

Zach Klaassen: Right.

Louise Emmett: So if we have a super sensitive technique that has two to three times the intensity of other standard agents that are out on the market now, and has a delayed image capability such that we can get rid of all the bladder activity, are we going to have better detection rates? Are we going to have better differentiation of local versus distant recurrence and biochemical recurrence? So that's something that I really would like to see. I would like to see how it compares to standard imaging agents in biochemical recurrence and whether we can actually better improve patients' outcomes by being able to stratify them into local versus distant. I actually think that we need to iterate on what we have already.

Zach Klaassen: Yeah.

Louise Emmett: PSMA is a great target, but I don't think we are there yet in terms of finding the optimum agent, and I'd love to see how copper performs.

Zach Klaassen: Yeah. Great answer. It's been a great discussion. Maybe a couple of just quick take-home points for our listeners.

Louise Emmett: Couple of take-home points?

Zach Klaassen: Yeah.

Louise Emmett: So this is a novel PSMA target. It's got the potential of being able to do delayed imaging and also more intense uptake within the cancer cell because of its bifid pathology, its bifid double-leg structure. It's looking promising in the phase 1 study. The phase 3 study is a registration trial, and we need to really finish that as quickly as possible to see how it compares to all the other agents out on the market. I think it has potential.

Zach Klaassen: That's great. Thanks so much for your expertise, Louise. Always great chatting with you and thank you for your time.

Louise Emmett: Thank you.