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Amir Iravani: Thanks, everyone. I'm really humbled to be here, and an absolute pleasure. So I have to keep on time. So this is my disclosures. And does it really matter, the PSMA agents that we're using currently in clinical practice? So I'm talking about initial staging, biochemical recurrence, and patient selection for PSMA RLT. And at the end, I'll be touching on what really matters.

So initial staging. So for the initial just brief overview after Dr. Pomper saying that, from 2020, we've had-- every year, we had one agent being approved by FDA, either diagnostically or therapeutically, starting from UCSF/UCLA study of PSMA-11, followed by DCFPyL in 2021, and, 2023, rhPSMA-7.3.

And we've come a long way, as Dr. Pomper noted, that when it was trained in 2014 from-- I was on the other part as a receiver of the great work that was done. And our faculty or our attendings showing these images of small-molecule agents to the urologists and telling them that you don't really need nuclear medicine physicians or radiologists to interpret these images. But turns out you still need us to interpret these images.

And now, more recently, we have a couple of other agents, copper-64 agents that are labeled to the different PSMA ligands that all-- they are in phase III registry trials. Looking at the trials in initial staging is relatively straightforward. The primary endpoints have been sensitivity and specificity of the detection of lymph nodes in pelvic lymph nodes. And the standard of truth always has been histopathology.

So when we look at the performance characteristics of these three agents, we see high specificity and modest sensitivity across all three agents, which is expected given considering the PSMA. And PET has a special resolution by our PET scanners and not necessarily-- and not pathologically and not disease.

In biochemical recurrence, looking at the three trials, it's a little bit more complicated because the primary endpoint has been changing over time and has been a work in progress. So the PSMA-11, we see there was a positive predictive value. As we moved on to the CONDOR trial, for the PyL we see that the correct localization rate was the primary endpoint, which was basically positive predictive value at the location.

And then to rhPSMA, we see there another co-primary endpoint was introduced by FDA, which was a verified detection rate, which is a product of positive predictive value and detection rate at the patient level, and then, at the regional level as well, another complex primary endpoint. And the other complicating factor was that the standard of truth in these trials was a composite of histopathology and imaging. And the imaging which was used basically was less-sensitive imaging, which-- and 80% of the patients use that endpoint as to prove.

But if we look at the subgroups that they had histopathology, which is only a fraction of those patients, which is possible to get the histopathology, we see relatively similar performance characteristics of high positive predictive value. So still similar performances. So really what comes to consideration and begs the question is, is there really a need to have multiple large-scale clinical trials for every PSMA PET that we are going to have in the future to prove the performance characteristics.

If basically we prove the performance characteristics in one trial, do we need to really prove it in the other settings from initial staging to biochemical or later? And why can we use PSMA PET now? It's been established. And it's been widely accepted by the physician and patients, not-- as a standard of truth, rather than a less-sensitive imaging.

So comparison across the PET agents. So we see this is the same patient-- this is the same patient that had all three agents, relatively similar biodistribution. And we see there are some minor changes. I'm showing in the liver. You see a similar uptake in the bone metastasis.

And then there's a little bit of change, particularly with the rhPSMA with low urinary activity, which was also-- in early human studies, we looked at lower cumulative proportion of the agent in the urine at two hours and at different time points compared to the DCFPyL. And that was also shown by Dr. Kou in pooling the SPOTLIGHT and LIGHTHOUSE studies. And majority of the patients appear to have a moderate amount of urinary activity. And the question is whether this impacts the clinical interpretation, particularly at the prostate bed at very low PSA levels.

So what about the novel PSMA agents? So the copper 64 has been used now in a couple of agents. The advantages is that it has a longer half-life, can produce a longer shelf-life. And delayed imaging is possible up to 24 hours after the imaging. And potential theranostic application if it's combined with copper 67.

There are disadvantages or challenges, as well, with the lower positron abundance of 18% compared to over 80% in gallium 68 or F-18. And consideration is-- and also, a different chelator needs to be used to make a stable compound, particularly if the over-three-hours imaging is desirable.

So this copper-64 PSMA I&T is currently in two phase III trials-- SOLAR-STAGE and RECUR. It's currently recruiting patients. And copper 64-SAR-BisPSMA, as well, has a particular structural molecule which has a two-binding motif for binding to the PSMA, which causes higher affinity. So this agent also is in phase III, in primary staging, and the plan to go to the biochemical recurrence, as well.

So what about patient selection of PSMA RLT? Does it matter which agent we use? Currently, most of the institutions in the US and across the world are using the liver as an organ of reference for selection of the patients. And so it's important to see whether the uptake in the liver is different between the agents.

So this study was done at Peter Mac a few years ago. And visiting Dr. Ferreira, a visiting fellow from Portugal, he came and did the intra-patient comparison, but basically showed that the liver uptake is actually the most consistent across-- in between the patients. And intra-patiently, also, it's very similar between PSMA-11 and DCFPyL.

And a group from UCSF looked at whether it actually impacts the outcome of the patient if you choose to use either of these agents. And although this is not within the same patient, but basically it provided similar results, showing the similar uptake in the normal organs and even in the metastatic sites.

How about rhPSMA? This is our early experience. And as we're collecting the patients who have both agents and looking at the normal organs, for the most part we see relatively similar uptake in the normal organs of reference. In a relatively few number of patients, we have the liver uptake. It's slightly higher, but I'm not sure whether it actually impacts our selection of the patients.

And as expected, the urine activity is lower. And this is a true example of patients that had both agents. Although the patient progressed between the scans, it really didn't matter for us to choose the patient for treatment.

So what matters most? I think it's clear now that the PSMA PET is more accurate than conventional imaging at various stages of prostate cancer. It was proven initially by the pivotal study ProPSMA, led by Dr. Hofman, and then in the biochemical recurrence, we see. And now is introducing a new paradigm of non-metastatic, which is becoming now metastatic by the PSMA PET, which is refining and redefining our disease status in the prostate cancer.

And the reality is the clinical adoption by the patient and the physician has outpaced the evidence production and evidence generation to measure the outcome of the patients. So what matters most, really? I mean, the sensitivity and specificity are defined by the people who actually interpret the images.

I mean, we are in the real-world clinical practice. We are outside of the clinical trial. The images are interpreted by the three expert readers. And it's very important to have a robust training and a standardized reporting. And the SPARK initiative is one of them that hopefully will have consistent reporting across the imaging so we get the robust results.

So really, does it matter which agents, currently out of the three? For the most part, not. But it is important to have the quality interpretation. This has been entered into appropriate use criteria led by Dr. Jadvar and Dr. Hope and also is now entered into the NCCN guidelines, as well.

And I'll just leave you with a message from a patient that basically is a prostate cancer patient and advocate, that his life got impacted by the PSMA PET. And I'm hoping that this is going to be the future. Thank you very much.