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Robert Flavell: All right. Well, thanks very much for the kind introduction, Tom. Let's see. I'll just wait a sec here for the slides to come up.

All right, thanks very much for the introduction. So, as Tom mentioned, my name is Rob Flavell. I'm a physician scientist here in the Department of Radiology and Division Chief of Molecular Imaging and Therapeutics. Depending on how you look at it, I either have the easiest talk or the most difficult talk for this conference, which is the topic of PSMA Primer: The Background. The material here is intended to be introductory, to hopefully set the stage for some of the more advanced material that we'll be discussing in more detail later on in the conference.

I have a few disclosures. Since the material I'm talking about in this lecture is more introductory in nature, they're not specifically related, but I thought I'd show them anyway. So, PSMA-targeted imaging and therapy, this is a game-changing theranostic strategy, and this owes to high target expression of prostate-specific membrane antigen across the prostate cancer disease course. PSMA PET is now standard of care for imaging of newly diagnosed high-risk prostate cancer and in biochemical recurrence after definitive treatment.

And also, more recently, it has become standard of care for treatment using lutetium PSMA in post-chemotherapy metastatic castration-resistant prostate cancer. So, the goal of my lecture today is to review the basics of PSMA pharmacology, how it is employed in the clinic, and a little bit about image interpretation for PSMA PET. So, for my lecture, I'm going to start by introducing PSMA as a target for theranostics and talk about the Glu-Urea-Lys pharmacophore, which is the common motif for all these small molecule agents that we're using in the clinic.

We'll talk about where PSMA PET and radiopharmaceutical therapy fits into the standard of care across the prostate cancer disease course. I'm going to explain the basics of PSMA PET imaging, including the normal biodistribution. And I'm going to talk about typical patterns of metastatic disease on PSMA PET. So, this is the molecule that we're all here to learn about, Prostate Specific Membrane Antigen. It is a 100 kilodalton transmembrane type II glycoprotein that is expressed highly on prostate cancer and to a lesser extent in the neovasculature of other tumors.

It also has a normal pattern of expression on normal prostate and other epithelial tissues. It may be targeted by small molecules which are principally directed against the enzymatic active site, and it may also be targeted by antibodies which are usually against the extracellular domain. So, the small molecule agents, which are what the lion's share of the work, including the FDA-approved agents are used, are based around the Glu-Urea-Lys-based scaffold. On this slide, which I took from a recent review article, they're depicted in red. Let me see if I have a pointer here.

Yeah. So, you can see this is the Glu-Urea-Lys, and it's common in all of these molecules. The advantage of this is that this binds nicely into the active site of the enzyme. One of the reasons why this is such a versatile pharmacophore is because you can modify this lysine with a number of different substituents, and it will still bind nicely in the active site. So, you can append a variety of different substituents to achieve your desired imaging or therapeutic outcome. So, positron-emitting isotopes such as F18 or gallium 68 may be appended here for imaging, and alpha or beta-emitting isotopes such as lutetium 177, actinium 225, etc., may also be appended for therapy.

And so, some of the more commonly used examples here are PSMA 11 with the HBED chelator and gallium 68, DCFPYL with F18, and then PSMA 617 with the DOTA chelator labeled with lutetium 177. You'll see they all share this common pharmacophore. It is important to note that even though there is some versatility there, changes in the imaging and therapeutic payload can have a substantial impact on affinity and delivery. Dr. Finler will talk a little bit more in detail about how the biodistribution of these different agents is modulated by these side chain changes.

So with that, let's switch gears and talk a little bit about how PSMA PET and radioligand therapy fit into the prostate cancer disease course. This is clearly an oversimplification, and prostate cancer is a highly heterogeneous disease, which can present with a variety of spectrums ranging from low-grade indolent disease to very rapidly progressive. But this is an example of how it might fit into the course of a single patient. So typically, a patient might present with a symptom or an abnormal PSA test that prompts a diagnosis of prostate cancer.

If the cancer is high enough risk, the patient will be recommended to undergo definitive therapy with either radiation or surgery. Particularly for high-risk cancers, this is a good time for PSMA PET to be used to detect metastases. A subset of patients at this point will have metastatic disease, and that can alter their management. So following definitive therapy, most patients will have a drop of their PSA to zero or to a nadir if it's with radiation to a low level that stays there. Many patients at this stage are cured.

Unfortunately, there is a subset of patients who go on to relapse in a setting called biochemical recurrence. What's happening here is the PSA levels start to rise, indicating that the prostate cancer has recurred. This is perhaps the most well-validated setting for the use of PSMA PET, and it's very effective here for detecting sites of metastatic disease that might be occult with standard imaging such as CT or bone scan. So for these patients, they will go on to elect treatment with what traditionally would be salvage radiation and hormonal therapy.

But increasingly, a role, and this will also be highlighted in one of the lectures later on in this conference, is metastasis-directed therapy where PSMA PET detects a lesion, and it can be radiated or treated with another focal therapy. So following these treatments, again, many patients will have a sustained period of remission, but unfortunately, there's an additional subset that will go on to progress to a state called castration-resistant prostate cancer or CRPC. This is a more aggressive form of the disease, and these are unfortunately many of the patients who do go on to succumb from prostate cancer.

This is a very dynamic area for new drug development. I've listed some of the therapies here. Perhaps the most common sequence of treatments that might be used in this setting would be androgen signaling inhibitors, abiraterone, enzalutamide, followed by chemotherapy such as docetaxel. This is the setting in which lutetium PSMA treatment is now FDA-approved for in this post-chemotherapy, metastatic castration-resistant prostate cancer. So, following the sequential treatment with hormonal therapy and chemotherapy as well.

And this is a good option for patients at this stage. We'll be talking a lot more about this. I believe the therapy talks are scheduled for tomorrow. So, this is just to set the stage for the current setting in which PSMA PET and PSMA radioligand therapy are approved as standard of care. We're going to be talking a lot more about emerging indications and moving these tests and treatments into different parts of the prostate cancer disease course.

Now, it's important to note that the concept of lutetium PSMA treatment is intrinsically paired with imaging, and this is one of the fundamental tenets of the theranostic concept. So, you may ask, why do you need to do the imaging before the treatment? Well, the reason here is that it's a highly effective method of demonstrating that the target is expressed uniformly across the disease, and it's a very effective predictive tool for seeing if patients will respond to therapy.

So, in this theranostic paradigm, a patient who is being selected for lutetium PSMA treatment first undergoes a PSMA PET. If they have appropriate target expression as visualized on the imaging, then they may be selected for therapy. It's also interesting to note that PSMA PET may be used as a response metric in this category as well, and there's some emerging research on that too. Okay. So now let's talk a little bit about the basics of image interpretation for PSMA PET. This is the normal scan.

When I'm teaching my residents about it, I sometimes call it the "clown" or the "scary clown" appearance. I don't know if anyone else sees it, but I feel like these silly mnemonics or analogies can sometimes help people remember things. So, the lacrimal and salivary glands definitely have prominent uptake. This will play a role as well in the toxicities of PSMA radioligand therapy. Other areas of common uptake include the spleen, liver, kidneys, small bowel, and bladder. Although it's important to note that this normal biodistribution can change somewhat with the different agents.

This is gallium PSMA 11. Some of the other agents look a little different. Another important normal site of uptake includes the celiac ganglia. These are small structures that are located in the retroperitoneum adjacent to the takeoff of the celiac artery. If you look closely on the scans, you'll see them in virtually every patient, depending on the resolution of your scanner. They can sometimes be brighter on one side or unilateral, but they look like these thin little slips of tissue adjacent to the takeoff of the celiac artery and commonly have some uptake in there.

So, not to be confused with metastatic retroperitoneal lymph nodes. There are many other ganglia in the human body. This is the one that I personally find the most tricky in some cases when interpreting PSMA PET. This is the presacral ganglion. It's located immediately anterior to the sacrum near the sacral neural foramina. You can see here this very small slip of tissue that has some uptake on the corresponding PET exam. When these are symmetric and mild in uptake, it's very simple to dismiss them as celiac ganglion.

Occasionally... Sorry, sacral ganglion. Sometimes they can be a little asymmetric, in which case you can probably still dismiss it. On occasion, there is a case where it's very bright, and you may wonder if it's a lymph node, but in most cases, you can comfortably dismiss these as presacral ganglion. Another one that you'll see in most cases, if you look for it, is the stellate or cervical ganglion. These are at the base of the neck. They don't really present much of a diagnostic dilemma because this would be a very unusual site for an isolated prostate cancer metastasis.

So, let's look a little bit at typical patterns of disease in PSMA PET. The most classic, of course, would be newly diagnosed prostate cancer where we can see some uptake right in the prostate gland itself, referring to the patient's primary prostate cancer. If this is a patient who's had a prior prostatectomy or radiation or something like that, then this would indicate the presence of a prostate bed recurrence. Another common pattern of disease is oligometastatic disease in the bones. This is an example of a patient who had three small metastases in their iliac bone.

These patients might commonly be referred for radiation therapy for their oligometastatic osseous disease. Another common pattern that can be seen is pelvic and retroperitoneal lymph nodes. So, you can see here this classic pattern of lymph nodes creeping up the pelvis into the retroperitoneum. Very classic distribution. Lymph nodes that have significant uptake in this region are essentially 100% guaranteed to be metastases, and typically they'll start in the pelvis, ascend through the retroperitoneum before going up into the thorax and other sites.

And this is another pattern. This is a patient with diffuse osseous metastatic disease. This is more characteristic of what you might see in a patient who's being considered for lutetium PSMA therapy. And you can see here this particular patient has very bright uptake in the bones, significantly brighter than both the liver and parotid glands, indicating that this patient is a good candidate for PSMA radioligand therapy and may benefit from that treatment. So, that brings me to the end. I'm going to conclude with a few take-home points.

PSMA is expressed in most prostate cancers. The glutamate urea lysine pharmacophore allows targeting of PSMA using diagnostic PET imaging and therapeutic isotopes. PSMA PET is standard of care for initial staging in high-risk prostate cancer and also at biochemical recurrence, and PSMA treatment with lutetium PSMA 617 using imaging selection with PSMA PET is a newer standard of care option in patients with post-chemotherapy metastatic castration-resistant prostate cancer. And then, common patterns of disease on PSMA PET include prostate recurrence or primary tumor, lymph node and bone metastases, with other sites such as visceral disease typically occurring later in the disease course.

So, I'd like to thank you very much for your attention. I think we'll save questions for our panel discussion and hopefully set the stage for the rest of the conference for you.