Zachary Klaassen: Hi. My name is Zach Klaassen, a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Sherief Gamie, who is a nuclear medicine physician at UC San Diego. Today, we're going to be discussing one of Dr. Gamie's presentations at the Interdisciplinary GU Cancer Forum, which was held in St. Petersburg, Florida, in June 2025. We'll be discussing the impact of molecular targeted imaging in CRPC and specifically theranostic implications. Dr. Gamie, thanks so much for joining us on UroToday.

Sherief H. Gamie: Thank you so much for having me. Very excited to be here. OK, so this is an area of medicine that I have a really keen interest in relating to my previous training and practice currently. So I did a little bit of hybrid training between radiation oncology and nuclear medicine and targeted therapy in rad onc, one of the areas that I have a keen interest in. So today I'm delighted to get a chance to talk to you guys about the impact of molecular targeted imaging on CRPC and the theranostic implications of those targeted imaging modalities.

So just to start out and just to put things into perspective, about 27% give or take of all cancers diagnosed on any given year are probably of prostate cancer origin. And if you see the breakdown of that 27%, most of them will be local stage I, stage II diseases. And that's the great majority of those diagnoses. And the not so great majority, about 16% are stage III and stage IV disease. And the reason that distinction is made because it actually has pretty significant implications as to how these patients will be treated. And as the urologists, probably know way more than me, what they'll do next with depending upon the stage of disease at the time of diagnosis. It's very important to make that distinction early on.

So first and foremost, I think it makes sense to identify what castrate-resistant prostate cancer means. And different guidelines will actually more or less distinguish between the castrate-resistant prostate cancer versus non-resistant prostate cancer diagnoses. So NCCN guidelines basically talk about CRPC as it relates to any progression in radiographic or biological markers, where the European entities will take a little bit of a different approach looking at the testosterone levels being under 50, but either biologic progression or radiographic progression or both.

And then the Australian model looks at rising PSA despite medical or surgical castrate testosterone levels of less than 50, but could be both radiologic evidence of metastatic disease or patients who have had prior chemotherapy-based docetaxel-based therapies. So very important to make sure that we clearly define what the prognostic value of PSMA assessment at the diagnosis. PSMA is prostate-specific membrane antigen, and it is an antigen on the cell surface of cancer cells. And identifying those antigens actually significantly impacts both progression-free survival, radiologic-free survival, as well as five-year recurrence-free survival.

And so in a five-year recurrence-free survival, we see that 88% give or take, 74%, 67%, and about 27% of patients exhibiting no low, medium, or high-grade or high amounts of PSMA expression. Preoperatively actually dictates how well these patients will do for the next five years. And so identifying those patients early can actually help us figure out which diagnostic measures to use and therefore what to do next about their treatment. So PSMA is basically prostate-specific membrane antigen. It's a type II membrane protein originally characterized in mouse monoclonal antibodies.

I don't mean to get too technical in this description, but you'll understand why I'm getting that technical because we will use this PSMA protein in different regions to actually try to figure out how to image both initially at the time of diagnosis and then thereafter if a patient is developing biochemical recurrence. So these tumor markers, some of them are intracellular, some are seen along the transcellular membrane, and most of them are actually extracellular. And so PSMA is expressed in neovasculature in other cancers. And so it's very important to make sure that we are using an antigen that can actually clearly distinguish prostate cancer from other types of cancers and not make it more confusing.

So the only cancer that we were able to identify, well, the two cancers that were identified at this point, they would have PSMA receptors, but very, very, very low amounts were kidney cancers, as you see here, and then triple negative breast cancers. So generally most other cancers that you will come across will really not have a whole lot of PSMA expression on their surface or PSMA antigen expression on their surface, other than very low amounts in kidney and in triple negative breast cancer.

This is an image of a study that we used probably back in the late '80s, early '90s, which was called ProstaScint. And it used that prostate-specific membrane antigen. And we labeled it with a radiopharmaceutical known as indium-111, which was a fairly good idea at the time. However, the images, as you can see, are fuzzy looking. And this is way back when, again, late '80s, early '90s when this was all we could get. As we developed technologically and were able to marry SPECT and CT, we were now able to get some anatomy into terms of some of these lesions that were lighting up on the scan.

We could never really identify exactly where they sat, but with the addition of or the fusion of SPECT/CT we are now able to move forward in terms of being anatomically able to localize a disease. But again, we're using a radiotracer that is very nonspecific with very high background activity and then poor tumor penetration ability. And so that's where we were probably through the '90s into the early 2000s.

And then as that technology evolved and we were trying to figure out new ways of trying to label some of these surface antigens, either through leaky vasculature or having nanodroplets that were tiny enough to seep through the vascularity and label some of these receptors internally or intratumoral, we're now better able to see these images or see these tumors in terms of defining their exact location, defining their exact extent, but also now making sure that they have those receptors on their surface if we were going to target those receptors with therapy.

So getting into the PET/CT realm of things, now we've moved from SPECT/CT to PET/CT and looking at the diagnostic portion of theranostics, where we looked at different tracers that we could use to try to target some of these receptors, looking for the radioactive drug, the linker, the receptor, and then on the surface of the tumor. So we had metabolic agents like FDG, which is fluorodeoxyglucose. This is based only on the fact that tumors have a faster doubling rate and therefore use more glucose, and in doing so, we could see them better on scans or on images.

The next step was Axumin, which is a tracer that uses an amino acid. And it basically targets knowing that prostate cancer cells use amino acids to replicate and therefore would have a higher rate of replication, and therefore a way or a means by which we could target those receptors and image them. What we're here to talk about today is the density of the prostate-specific membrane antigen that we used carbon-11 acetate or prostate-specific membrane antigen. And this is really the one that we're going to focus on. We use some tracers that look very much like the bone scan agents but actually were PET agents and gave us better resolution images.

And then the least we use for prostate cancer is somatostatin receptors. And this uses a neuroendocrine tumor-based somatostatin receptor analog. And these patients typically don't do very well. And generally, we use this tracer for patients with neuroendocrine tumors of pancreas of the GI tract. And we will sometimes pick up lesions in the prostate. And so I meant to add it here but not really a scan, if you will, that you would do for prostate cancer patients.

So this is an example of how well we've or how much better we've gotten at trying to image either localized disease versus metastatic disease. So this is an 81-year-old patient who was treated for prostate cancer probably about six years earlier PSA nadir. And now their PSA is rising again. And we did our usual bone scan. Urologists usually try to start out by doing the good old bone scan to try to figure out if this patient has metastatic disease. And really, all you can see here is all these two tiny pixels, if you can squint hard enough and see them on the ribs. And then lo and behold, you do a sodium fluoride PET scan for this same patient.

And there are the two rib lesions, but there are several other lesions that clearly define that this patient has metastatic bone disease from prostate cancer. And so as we got better with the imaging modalities, we got better at finding smaller lesions, probably making the urologist life a little more difficult because now, there are several lesions to try to get at, but at least it set them in the right direction in terms of what they should do next, based on the fact that this patient more likely has widespread metastatic stage IV disease.

This is a nice example of one of the patients, a very similar example to the prior patient, where they tried an FDG PET scan versus a PSMA PET scan. Same patient treated PSMA nadir and then the patient coming back with rising PSA. And clearly you can see the extensive amount of disease that you can see on the PSMA PET scan compared to the FDG PET scan in this case. And so as we got more specific about targeting antigen or receptors on the surface of the cancer cells, we're better able to figure out whether these patients have metastatic disease, whether the metastatic disease is localized to the pelvis or beyond the pelvis, and then obviously the extent of the metastatic disease.

This is another type of PET/CT that we use called F-18 Axumin. This tracer uses an amino acid called L leucine. And basically, just as I mentioned earlier, this is looking for prostate cancer cells that are doubling using the amino acid that this tracer targets and basically being able to try to pick up lesions. And so in this case, if you look at the whole body images, really you don't see much in the way of metastatic disease. But with the, again, with the fusion of PET/CT, this patient clearly has lymph nodes, left pelvic sidewall lymph nodes, left external iliac lymph nodes that are clearly PET positive that help make the diagnosis. In this case telling the urologist that the patient has metastatic disease within the pelvis. But again, it's gotten out of the prostate.

And then I like to use this slide to put side by side an image of what FDG PET looks like versus C-11 choline versus now the more commonly used PSMA PET scans for initial diagnosis and then follow-up or restaging of patients after they've been treated. I'm going to go one step further and talk a little bit about PSMA PET/MRI. Because this is an area that is rapidly growing and an area that I think is going to change the diagnostic characterization of what we do on the imaging side. So we talked a whole lot about PET/CT and PSMA PET/CT, but now I think I want to take the discussion a little bit further and talk about PSMA PET/MRI.

Whether you have a PET/MRI piece of equipment in your location or in your institution, or if you use fusion software that's going to help you fuse PET and the MRI, most patients will always probably get an MRI at time of initial diagnosis. So it's not that we're adding new scans or new studies. It's that we're utilizing scans that we would have done anyway, but actually trying to use those to help direct therapy and to help clearly define the patient's stage at the time, but also to define what we're going to do about it. And so PET/MRI is becoming a huge area in specific to prostate cancer, but in other areas as well.

And as you can see here, now that we have the morphology, if you will, that MRI is so good at defining and superimposing that MRI image with the PET image and clearly defining where the activity is. And so in this case, if you were on the fence about capsular infiltration, you probably have your answer by fusing these images. If you were on the fence about whether this lymph node being so tiny outside the prostate was positive or not, it's a sub centimeter sized lymph node on the MRI that could go either way. But now that you can fuse the PET and the MRI, you clearly define that this is a positive lymph node, and the fact that you might see things within the prostate that don't end up being PET avid. And so clearly it can either upstage or downstage a patient initially and define areas on the MRI that may not necessarily warrant the urologist do anything about it.

So to summarize and this is going to be several slide summary that talks about the application of PET/CT and PET/MRI, specifically PSMA PET/CT PET/MRI, is very relevant to the urologist and a lot of new studies. Actually some studies that I'm personally aware of coming out of UCLA where the urologists are actually using lesion-targeted local procedures. So based on whatever the PET/MRI is defining as the lesion, they are targeting and localizing their therapy to that specific lesion. And it's also impacting the radiation oncologists in terms of what they do because now they can do lesion-specific external beam radiation therapy boost. And so if this patient were, for instance, to get treated with external beam radiation therapy to the pelvis or to the prostate using IMRT or what have you, you can go back and actually boost this lesion with an extra dose of radiation to try to get it, making sure that you hit a tumoricidal dose as far as the tumor.

And the next step is application of PSMA PET scan and its impact on therapy. And so if we're able to identify a linker, we can put a radiotracer, tag it onto it, and we can identify the receptor on the surface of the cell. We can use different radio diagnostics to get an image like gallium PSMA like F-18 PSMA. And then after you've done that and after you've been able to actually localize this cancer and identify it, you could use that same linker to add to it or to link to it a therapy dose of radiopharmaceutical that would deliver targeted therapy. So basically you would be doing an intravenous infusion of a liquid that is targeting a specific receptor on the surface of the cell of the prostate cancer cell and delivering a therapy dose to that receptor based on the fact that you've identified that receptor on your diagnostic portion, and you know that the cancer is PSMA positive or expresses the PSMA antigen on its surface. So I'll move to the next there.

And so using the therapy part of the theranostics. And we've now identified probably two or three different radiotracers that we are using to target prostate prostate-specific membrane antigen cancer cells. The one very common one that we all know is the lutetium-177. That's both a beta and gamma emitter. We have radium-223, which is an alpha emitter. We use that specifically targeting bony metastatic lesions from prostate cancer. And then there's a whole new area of research that we are currently. We have probably about six or seven clinical trials currently using something called actinium-225, which is an alpha emitter.

And so we have the ability to use different radiotracers to target that. I'll quickly talk about the single study that was fully published after about a two to three year follow-up. At this point, the VISION trial and the lutetium-177 PSMA-targeted therapies have now improved overall survival in patients with castrate-resistant metastatic prostate cancer from about 3.4 months to about 8.7 months. I won't go through the details of the side effects and so forth, but, again, we have seen an improvement in survival at this point using this radiopharmaceutical. And so the question is if we can use other radiopharmaceuticals or other tracers, can we get better results?

Quick look at a patient that there was sequential imaging between doses after each dose of lutetium-177. Clearly the patient has extensive distant metastatic disease that you can see here with time and with subsequent doses, where mostly resolving and intensity wise, even the ones that are remaining are significantly less active compared to the initial study. And so looking at that, we can say that we have improvement of quality of life and some improvement in overall survival.

And so basically, we are now working in a continuum of prostate cancer staging, restaging, and therapy. Identifying the PSMA antigen or receptor on the surface of the cancer cell early will help direct which tracer we can use. And if we have identified it, then this potentially makes a patient a candidate for directed therapy, using either lutetium or using actinium, or what have you to target these cancers.

One last area I want to do, I want to make sure I mention this. This is depending upon your interest. This is how you shield the patient that has been treated with radioactive material. So like I mentioned, lutetium-177 is mostly a beta emitter. A sheet of plastic is sufficient, more than enough to keep the patient or the family members around the patient safety safe after you've treated them and discharged them to home. And actinium, like you remember, I said it was an alpha emitter. There's really no shielding that's needed. You can treat the patient, send them straight home. No precautions. No worry about exposure of the public to any radiation after their treatment.

One last area that I personally have an interest in is dosimetry. Looking at patients after we treated them and figuring out how much radiation we've delivered either to the lesions or to the critical organs like the kidneys, in this case like the bone marrow. And so we do post treatment dosimetry, whole body SPECT/CT images. And we actually measure how much of the dose that we administered was delivered to the lesion. The reason for this is currently we're working under the assumption that every patient gets a single dose of 200 millicuries per infusion. And doing that is more or less unclear as to whether that's the best approach.

So using dosimetry can help us figure out dosage. Initially, we can figure out how much of a dose to use initially and can we go beyond six doses. Because if we're giving a smaller dose per infusion, then we may have room to give more doses if the patient looks like they're responding favorably, their PSA looks like it's responding favorably, and their images look like they're responding favorably. Thank you very much.

Zachary Klaassen: Sherief, fantastic presentation. I love the historical background too for the UroToday audience. I want to take a minute, because it's great to have nuclear medicine physicians on these kind of recordings, just to get your guys' take on when we're thinking about patients, they may have had two or three or four PSMA PET scans, whether it's in the staging setting or if it's a biochemical recurrence or getting into the CRPC setting. When should we be thinking about timing of sequential PSMA PETs, particularly when they're on therapy for CRPC?

Sherief H. Gamie: That's a great question, and I appreciate the opportunity because as you probably well know in your practice, it's not easy to get a PSMA scan every single time you've given a dose. And so there's some things are dictating the paradigm that I don't know if they necessarily are the correct approach to approaching or taking care of these patients. If you were to ask my personal opinion, and this is what we're doing in a new clinical trial that we're doing at UCSD, we're getting a sequential or getting sequential PSMA scans three doses in.

Zachary Klaassen: OK.

Sherief H. Gamie: So we're following PSA, as I'm sure you're aware and that's probably what you're doing. PSA is after each dose, no question. But we're getting a PSMA scan three doses in.

Zachary Klaassen: Got you.

Sherief H. Gamie: And it depends on who you talk to because even if you do the scan, the PSMA scan three doses in. And let's say the images are not appearing to have shown significant improvement, but you're seeing PSA dropping or nadiring, and I don't know if it's going to impact whether we end up continuing treatment versus not, but it's at least having a baseline midway marker. It makes a whole lot of sense. So I would say not after every single dose, but probably three doses it makes a whole lot of sense.

Zachary Klaassen: Excellent. And my final question is just relating to this. This is a huge area of interest for both diagnostic and theranostic. From a diagnostic standpoint, what agents are you particularly excited about maybe coming down the pipeline that you can share with our listeners?

Sherief H. Gamie: So I think we found we struck gold when we are now able to image PSMA as an antigen or as a surface antigen that's expressed on the tumor cells. And so most of the studies currently are still geared and focused at the PSMA antigen. But what we are changing is what radiopharmaceutical we are using to treat. If we're able to deliver a higher dose of radiation per particle, then that's one big takeaway. If we're able to make sure that the public is safe and we can treat patients to send them straight home, and the family members at home are safe, those are the things that are directing or driving some of the changes or some of the new clinical trials.

Lutetium-177 is a great agent. I think actinium-225 is probably going to change the landscape a little bit as far as that. And I think we're going to see a few more studies and more indications and drugs that are coming out that are actinium-225-based. And we're looking at a few hybrid-based that are not really-- at this point, they don't want to name them. They've given them a number which give off both gamma and beta because that helps us with the post-treatment scanning and dosimetry. So the one I'm most excited about is actinium-225. At this point we're able to get post-treatment scans, but it's delivering a bigger dose of radiation per particle, and therefore you're getting a higher dose to the lesion and a smaller dose or less of a dose to the critical organs, like the bone marrow, like the kidneys, like the liver.

Zachary Klaassen: Excellent. It's been a great conversation. Any final take home messages for our listeners.

Sherief H. Gamie: Take home message is it's a huge area, and a huge area of research currently in medicine. And the one very positive thing is for the very first time in prostate cancer, and I think you would agree to this, we're seeing some improvements in overall survival, which we hadn't seen. We were always looking at disease-free survival, progression-free survival, but a little bit of movement towards overall survival, which I think is a very promising area or a very promising direction in treatment of patients with metastatic prostate cancer.

Zachary Klaassen: Yeah, well said. Sherief, thanks so much for joining us on UroToday. Thanks for your time in the middle of your busy day.

Sherief H. Gamie: Thank you very much. I'm glad to be with you, and I appreciate the opportunity.