A Closer Look at PSMA PET: How Imaging Shapes Prostate Cancer Care

PSMA PET Imaging

PCF Chief Medical Officer Dr. Phillip Koo leads a conversation with medical oncologist Dr. Tanya Dorff and urologic oncologist Dr. Zachary Klaassen. Learn about PSMA PET imaging at key points in the prostate cancer journey.

• A new diagnosis of cancer that may be more likely to grow or spread 
• A rising PSA after treatment (biochemical recurrence)
• Advanced prostate cancer: How imaging shows whether radioligand therapy may be an option, and how the dose may be adjusted based on PSMA PET scan results

This program was produced with support from Lantheus.

Transcript:

Phillip Koo, MD [00:00:00]

You know, we’ve covered PSMA PET on multiple different webinars in the past and now we’re really focusing on how that information that we see on those tests inform the management decisions and we have two great speakers, panelists who really understand the disease very well who are going to fill this in for us. Before we get into the cases, we’ll just do some quick level setting regarding what is PSMA PET? And as we’ve heard multiple, multiple times, we know that PSMA is a protein that’s overexpressed in prostate cancer cells. So you have all these different proteins that are being expressed. And then you have this molecule that’s able to attach and give off this positron that can be imaged to create an image, to create a picture that allows us to figure out where exactly the disease is located and if you just swap off the one isotope instead of having a positron emitter you put like a beta or an alpha emitter all of a sudden you’re able to treat the disease as well and that’s why we’ve been so excited about you know this area of this called theranostics diagnostic radiopharmaceuticals whatever you want to call it but it’s really this idea of being able to see the disease and then treating it. And then let’s go straight into the cases now. So we’re gonna sort of go along the path of patients who are initially diagnosed and then end up with a case about a patient who has metastatic disease, advanced disease. So we’re gonna start off with case number one that Dr. Klaassen is gonna present regarding a patient at initial diagnosis, initial staging for high-risk prostate cancer. So Zach, let me turn it over to you.

Zachary Klaassen, MD [00:01:48]

Awesome, thanks Phil, always good to be with you and Dr. Dorff and thank you to the PCF for the kind invitation to jump on this webinar. And there’s a lot of information we can get on initial staging of high-risk prostate cancer. So this is a case of a 62-year-old newly diagnosed PSA is 12, so certainly elevated. He had a prostate biopsy. He had six cores of Gleason 4 plus 4 equals 8, or as the new terminology, grade group 4, one core of Gleason 4 plus 5 equals 9, grade group 5. And so based on this gentleman’s biopsy score, his PSA, he’s certainly a candidate for initial staging to see exactly what’s going on with his disease before we think about treatment options, whether it be surgery, radiation, hormone therapy, yes or no, et cetera. So important, totally asymptomatic. This is another call out for PSA screening. No bone pain, no weight loss. Other symptoms concerning for metastatic disease. PSA screening led to this prostate biopsy. Certainly, what we call real prostate cancer. This is something that needs treatment. And just fine-tuning where we are before we select a treatment option is really important.

So when we think about, Becky’s gonna advance the slide. Go ahead, yep. Why we order a PSMA PET scan. So this patient has what we call NCCN high-risk prostate cancer. So anything unfavorable intermediate risk or higher should be staged appropriately beforehand. And certainly in 2026, as we round to 2027, this is a PSMA PET scan, and thankfully the insurance companies have gotten a lot better at approving these scans before we get into therapy. Certainly, the process has become much more streamlined. This patient certainly qualifies with his grade group 5, Gleason 4 plus 5 equals a grade group of 5. He certainly qualifies for a PSMA PET scan. The reason we do PSMA PET scans now is because conventional imaging, whether that be bone scan, MRI, CT scan, it may miss some of these small lymph nodes in the pelvis. It may miss bone metastases. And this can really dictate how we think about the next treatment step. And so while conventional imaging has gotten us till about 2019 when we started doing PSMA PET scans, certainly in 2026, this patient should get a PSMA PET to really allow the discussion on treatment to be much more centralized to what’s actually going on with the disease. So, PSMA PET, it’s a one-stop-shop, single test, evaluates the prostate, the pelvic lymph nodes, distant sites, whether those be lymph nodes further up in the abdomen, whether that be liver, lungs, bone metastases, it gives us a full picture of what’s going on. And so I think the key here, identify if it’s positive, metastatic disease before treatment, because we know that roughly half or even greater than half of the cases will have a different treatment plan based on what the PET CT shows.

Next slide, please. So this patient, again, 62 year old, his PSA is 12. He’s got grade group 5 disease. He’s thinking, should he have surgery? Should he have radiation? Should he have treatment intensification with his radiation? And we see here on the left, this is active disease in the prostate. His SUVmax is about 14. So it’s kind of lighting up as we would expect. But what we see is a red external iliac lymph node. And so when I think about treatment options for this patient, if you’re thinking about a surgical approach, you wanna, at least from a surgical perspective as a urological oncologist, we wanna go for a potential cure. So maybe we know this one is positive. Perhaps there’s other ones that are positive that we can’t see on the PSMA PET scan. Maybe not the best approach. Maybe it is depending on what the patient’s goals are. Then we maybe bring into radiation therapy, ADT hormone therapy for a certain amount of time, even abiraterone given the fact that this patient has a positive lymph node. So it really allows that conversation to be much more streamlined based on what this PET scan shows.

Phillip Koo, MD [00:06:06]

Great. So thank you, Zach. So, you know, before we get into what you see and how it changes your management, there’s always a lot of questions on, should I even get a PSMA PET? And you talked about it, unfavorable intermediate or worse. That being said, I see patients coming in with favorable intermediate or maybe even Gleason 6, where they’re on active surveillance, often asking, should I get this test? And how do you approach those scenarios?

Zachary Klaassen, MD [00:06:33]

Yeah, it’s a great question. It’s something we see in the clinic all the time, and I think the easiest one is a Gleason 6. This patient needs an MRI of the prostate, not a PSMA PET scan. They need stratification perhaps with either a genomic test such as Decipher, maybe an artificial intelligence test with something like ArteraAI Prostate, but they don’t need a PSMA PET scan. So the favorable intermediate, that’s on the borderline. Still, we don’t have evidence that suggests we should get something like a PSMA PET scan for those patients. It’s really those Gleason 4 plus 3, the higher PSAs. Certainly, this patient we talked about needs one, but it’s not for everybody. And for the patients out there wondering about it, be glad that you don’t have disease that needs a PSMA PET scan. I think that’s the take home message.

Phillip Koo, MD [00:07:21]

And you know, the real value, as you mentioned, of PSMA PET is being able to detect disease when it’s spread to other parts of the body. That’s really obviously a critical fork in the road or decision point. Lots of different radiotracers are out there. What should patients know when they have these discussions with their doctors?

Zachary Klaassen, MD [00:07:44]

Yeah, generally the high-level take-home point is they all kind of work the same at this point. Whether it be gallium, whether it be fluoride, all the ones available kind of work about the same. So if your doctor says, I want to do this, that’s probably fine. There’s some interesting data that has been presented and not yet FDA approved with copper. Some of these isotopes can detect lymph nodes up to as small as two millimeters. That’s not prime time yet. Maybe it will be at some point in the future. But generally speaking, if you’re getting a PSMA PET scan, regardless of what the radioactive ingredient is, it’s gonna be fine. And I think that’s the message is if you’re getting one, you’re getting the right test.

Phillip Koo, MD [00:08:27]

Alright, so the patient goes ahead and gets one of these PSMA PETs because it’s appropriate and I think it’s easy if it’s normal, if it shows nothing, you sort of proceed as you normally would have with surgery or radiation. If it’s widely metastatic, then it’s pretty convincing and then, you know, the treatment paths are different. I think the challenge becomes sort of that middle ground and what do you do? When you see maybe a handful of mets, maybe just in pelvic lymph nodes, how do you sort of manage that and come to a decision on what the best treatment is for the patient when they’re diagnosed?

Zachary Klaassen, MD [00:09:04]

Yeah, I think the main thing is if this scan is negative, that’s great news. It’s the best available scan we have in 2026 to say, hey, we think your prostate cancer is confined to the prostate. So we kind of go back to the drawing board and say, locally confined disease, high risk disease for sure. That biopsy, Gleason score is real. Let’s talk about the treatment options based off a negative scan. Now, if it’s the one lymph node like I talked about, I’m probably talking about all the options, radiation, aggressive surgical treatment, but if it’s widely metastatic, probably bringing in Dr. Dorff. And so I think that’s where the multidisciplinary aspect is important because if as a surgeon, if I’m taking out the prostate, I want the best information to say that, hey, I can try to cure you with this operation. There’s a lot of side effects, which we’ve talked about on webinars in the past, but if we’re gonna go for the surgical approach, we wanna have the best information to try to make that a cure with one procedure.

Phillip Koo, MD [00:10:03]

Is there a magic number or cut-off with regards to the number of mets before or after which you might say, all right, surgery is off the table? The answer is probably no, but how do you sort of talk to patients about that?

Zachary Klaassen, MD [00:10:16]

It’s individual for sure, Phil. I think my bias is that if there’s multiple lymph nodes, I probably can’t cure you with an operation. And so, we know there may be a one millimeter that we can see on a histopathological diagnosis under the microscope that may never show up on a PET scan. But if we don’t take that one lymph node out, it’s going to be a PSA persistence after surgery. So my bias is, if there’s multiple, certainly I think the chance of a cure with surgery is pretty low.

Phillip Koo, MD [00:10:46]

All right, great. And then let’s say you have a patient who gets, who has diagnosis of prostate cancer, it’s Gleason, or grade group 5, they get a PSMA PET, they go to surgery, their PSA looks great. Do you keep following them with the PSMA PET CT?

Zachary Klaassen, MD [00:11:03]

Yeah, it’s a good question. In my practice, that patient’s had a very good result. They have a PSA undetectable after surgery. I’m following their PSAs every three months, at least for the first year. In that higher-risk patient, it may be every three months up to 18 months and then we’ll transition to six months. I won’t necessarily get a PSMA PET scan on that patient unless that PSA starts to go up. So I think that’s important that, Dr. Dorff’s gonna talk about getting imaging more regularly in the metastatic setting. If you’ve had a good, if you had a successful surgery, the PSA is undetectable, stays undetectable, PSA follow-up is more than reasonable.

Phillip Koo, MD [00:11:41]

And I think that’s a great, you know, teaching point for everyone to walk away with. You know, the PSA especially upfront is a really good marker. There’s no strong reason to do surveillance imaging with PSMA PET every year or whatnot. It really should be triggered by something else that is giving a signal that there might be disease recurring, which now takes us to the second case, which is biochemical recurrence. So walk us through that.

Zachary Klaassen, MD [00:12:09]

Yeah, so when we look back in the last six to eight years, there’s really, from a localized setting, there’s two indications for PSMA PET. One is the one we just talked about, intermediate risk, unfavorable intermediate risk or higher. Great indication, FDA approval. The other one is biochemical recurrence. So this is a PSA that’s increasing after local therapy. That could be radiation therapy, it could be surgery. And so this patient that I’m presenting here, this is a 71-year-old. Had his prostate removed seven years ago, his prostatectomy pathology, unfavorable intermediate risk, 4 plus 3 equals 7, grade group 3. What that pT2cN0 means is that there was no lymph nodes positive, it was confined to the prostate. Negative margins is something that the pathologist will tell us, because when we take the prostate out, we sort of do a standard procedure where we take the fat around it. If the marking on that whole specimen does not have prostate cancer, we call it a negative margin. We know that that’s a good prognostic factor for not having recurrence. Now, what’s interesting about this patient’s case is PSA undetectable for three years after he had PSAs every six months, or excuse me, every three months for the first year, then every six months for a couple years, then went to annual after that. But then we started to see a signal. He got referred to me when his PSA was 0.56. And so, clearly, when your prostate is removed, the PSA should be undetectable. It’s the only organ in the body that makes PSA. If it’s gone, the cancer is gone, it should be less than 0.01 on an ultra-sensitive PSA test. Importantly, another call out for PSA surveillance after treatment. There’s no symptoms associated with this. The patient’s doing fine. He’s seven years after surgery, but he’s diligent with his PSA checks, and that’s where we find the biochemical recurrence. Biochemical recurrence means we can’t necessarily see anything, we just have a blood test that tells us that, hey, there’s a signal going on here. Something’s producing PSA, the prostate’s gone, it’s likely a couple of prostate cancer cells that are making this PSA.

Next slide please, Becky. So understanding biochemical recurrence, as I said, when that prostate’s gone, we want that PSA to go to undetectable. We can’t say zero because the lab test has its own limitations, but ultra-sensitive PSA will tell us less than 0.01 or better. That’s what we’re looking for. Some labs will say less than 0.1. That’s fine. The older labs say less than 0.2. Most of them now will be less than 0.1 or less than 0.05 or less than 0.01. We want that number to be less than something. When we look at the literature and sort of how biochemical recurrence has been defined, the biochemical recurrence threshold after surgery has essentially been 0.2 or higher. And so, again, when we know that the prostate’s gone, there should be nothing making the PSA go up. We have to assume that those numbers are going up because of prostate cancer cells that are still present. So, a rising PSA suggests recurrence of prostate cancer, but it doesn’t necessarily tell us where it is or even if it’s identifiable on a scan, whether that be MRI, conventional imaging, such as CT bone scan, or more recently, the PSMA PET scan. So this patient’s PSA 0.56, still relatively low, certainly in need of additional investigation. At this level of PSA, the old school CT bone scan MRI does have some trouble finding the disease just based on the fact that these are very small areas if they are detectable that we can’t necessarily see on a CT or a bone scan.

Next slide, please. So just to recap, 71-year-old prostate taken out seven years ago, PSA 0.56 after surgery. On the left, we see a signal where the prostate used to be. We call that the prostate bed. This is likely a prostate cancer recurrence where the prostate was. And then when we look a little bit further up, going towards the head, we see left internal iliac lymph node lighting up on the PSMA PET scan as well. So this helps us, again, just like in the initial high risk for initial staging. This allows us to have focused discussions on what those next treatment plans are going to be based off of this PSMA PET scan.

Phillip Koo, MD [00:16:35]

Great. So, basically what you’re saying is if a patient starts increasing, has had surgery and then their PSA starts going up above 0.01, you would get a PSMA PET as soon as it starts to rise, is that correct?

Zachary Klaassen, MD [00:16:51]

Typically, I don’t want to get into the weeds too much. I’ll typically get consecutive results to see if it’s actually going up. If it’s a real test. I’ve seen PSAs go to 0.03, then come back down undetectable. So we want to see a consistent increase to suggest, hey, this is actually a real increase. We’re talking about very small numbers of PSA. So we don’t necessarily pull the trigger when it goes to 0.02, but if we see it go from 0.02 to 0.05 to 0.09, we’re starting to get a trend. And that’s where I think that the imaging, especially the AUA guidelines, which is our governing body for urologists, has now suggested if there’s an early recurrence, getting a PSMA PET scan before thinking about other therapies is certainly reasonable.

Phillip Koo, MD [00:17:36]

Great, and then some questions came in about patients who’ve received radiation treatment, not surgery, for their localized disease. At what trigger do you get a PSMA PET in those patients?

Zachary Klaassen, MD [00:17:48]

Yeah, so a true biochemical recurrence for radiotherapy is a little different. So the prostate is still in the patient, so there’s gonna be potentially still some baseline PSA that’s being detected. We wanna take the radiation number, the lowest number after radiation. So let’s say that’s 0.5. We call that the nadir. That’s the lowest number that the patient got to after they had radiotherapy. So a true biochemical recurrence happens when it’s the nadir, in this case 0.50, plus two. So the biochemical recurrence threshold would be 2.5 for this patient. So even though the PSA may be going up a little bit, that could be normal prostate, just making PSA, there’s still the prostate in the body, that doesn’t trigger anything until it hits 2.50 on consecutive readings. If that patient gets to 2.8, 3.1, 3.6, then we’re thinking biochemical recurrence after radiotherapy that would trigger the PSMA PET scan.

Phillip Koo, MD [00:18:42]

Great. So, all right, you get the PSMA PET scan, you’re labeled biochemical recurrent, biochemically recurrent. You get a PSMA PET and it’s negative. It doesn’t show a reason why the PSA is rising. And I think for some people that’s, you know, that could be good news, I guess from some perspective. It’s kind of bad news. But the management of these types of patients has changed over the past couple years. Can you inform all of us about some of what you’re seeing today?

Zachary Klaassen, MD [00:19:12]

Yeah, totally, I think this is a really important point for the people on the call. And I think the way I look at this is, let’s say your PSA is 0.15. You’re not quite at that 0.2. We want a negative scan. We don’t want to find anything because we know if we can’t see anything, at least on our best imaging that we have available, nothing’s detectable that’s localized either to a lymph node or in the prostate bed or heaven forbid in the liver or somewhere else. In those situations, it’s really important, negative scan, we have very good data, a series of trials published in the early 2020s, and then a conglomerate of all that data analyzed to tell us that early salvage radiotherapy to the prostate bed, where it used to be, is certainly available to help with not only a cure, but even long-term survival for these patients. So I think when we think about these situations, we’re getting that PET scan just to rule out something that may be outside the box. We don’t want to necessarily see that. If that’s negative, you still need radiotherapy to where the prostate used to be.

Phillip Koo, MD [00:20:16]

Great. Alright, so then let’s say you get the PSMA PET and it is positive. It shows certain number of lesions and nodes or organs or whatnot. What’s sort of the approach at that point?

Zachary Klaassen, MD [00:20:29]

Yeah, there’s a couple options here. I think this is where some of the trials that are still occurring are still gonna give us some more information over the next couple of years. We just had a really good presentation at one of our big meetings in Europe a couple weeks ago that in that situation, let’s say the patient has several areas, they should get radiotherapy, they should get ADT for two years, and they should get Nubeqa, or darolutamide, for two years. This was the DASL-HiCaP study. So, sometimes if it’s one little area, maybe we just hit it with a little bit of radiation. Maybe we radiate the prostate bed as well. It’s evolving when we see things on PET scan that we are sort of what we call outside the box, outside of where the prostate bed usually would have the recurrence. So I think these are individual treatment discussions that you should have with your treatment team.

Phillip Koo, MD [00:21:19]

And you know, there’s probably no rule of thumb here, but at what point are we looking at systemic therapies? And I’ll sort of get Dr. Dorff and Dr. Klaassen’s perspective on this. When do you need to start thinking systemic treatments? Is it five metastases, 10? You know, walk us through what’s going through your brains, maybe Zach, from your perspective, when you would send a patient to Dr. Dorff and maybe Dr. Dorff when you would like this patient to be referred to you.

Zachary Klaassen, MD [00:21:45]

Yeah, no, I think once we start getting things out of the pelvis, so sort of this delineation where the bones come together, if we start seeing multiple lymph nodes there, and then we see one sort of a little higher up, or we see something in the bone, then we’re probably delineating this patient as metachronous or after primary therapy, metastatic hormone-sensitive prostate cancer. So this gets into treatment intensification usually with ADT, which is the hormone therapy blocker, and an ARPI, whether that be darolutamide, enzalutamide, apalutamide, abiraterone. And so this is certainly a higher risk patient than say the patient that we just presented that has one lymph node. So that’s what I’m thinking about treatment intensification in my practice.

Phillip Koo, MD [00:22:30]

Great. And Tanya, your perspectives.

Tanya Dorff, MD [00:22:32]

Yeah, I think it’s increasingly complicated because we have these studies that have done focal radiation to sites that are picked up on the PSMA PET. They’ve done it without hormone therapy as a way or a goal of delaying or avoiding hormone therapy and then there have been combinations with hormone therapy which look like maybe a little bit more effective. But we don’t have a head-to-head comparison of that kind of approach versus using something like EMBARK where we use doublet hormone therapy, testosterone suppression with enzalutamide, one of the AR antagonists, which actually showed a metastasis-free survival benefit, overall survival. So I think we have to at least talk through with patients when we wanna use, let’s just focally radiate and watch you and try to delay hormones versus when do we really want to jump in and do more comprehensive? And it’s not only about number on the PET scan, it’s about location, it’s about those initial characteristics of the cancer, sometimes even genomics that factor into our decision-making.

Phillip Koo, MD [00:23:46]

That’s really helpful and I think there was a question that was submitted about this. So sometimes you can chase down all the mets, sometimes you can’t. There’s really not a clear, you know, cut off for that. There were other questions came in, you know, biochemical recurrence. We talked about that. Unfortunately, maybe 30 to 50 percent of all patients who are treated for their primary disease in the prostate, unfortunately, undergo biochemical recurrence. Hopefully, as now that we have better imaging, that number will decrease, but we’ll have to wait and see what the data shows us. And there was another question, comment about biochemical recurrence for patients who received radiation. And you’re right, the Phoenix criteria is what Dr. Klaassen and I talked about. And there are various ways to approach the definition of biochemical recurrence in these patient populations. So now we’re gonna shift to the use of PSMA PET in patients who have metastatic disease, advanced disease. And we’ll let Dr. Dorff present her slides here.

Tanya Dorff, MD [00:24:48]

Great, thank you. I did see a question in the chat about, if someone’s had CT and bone scan and they have metastatic disease and they’re getting repeated CT and bone scan, what does a PSMA PET add? And I think that’s really important. As Zach set up so nicely, we initially really studied PSMA PET as a way to find cancer in staging and rising PSA, but now that we have a treatment that works very similarly to the PET scan, which is lutetium PSMA-617, right? It’s a theranostic. The PET shows us where the disease is and where that disease is, the lutetium PSMA can land and treat the cancer. So, that’s where we start to use PSMA PET in the setting of advanced or metastatic prostate cancers. Really, in my opinion, when we’re starting to think about whether we want to use lutetium PSMA as a treatment. And so that’s kind of where I focused my cases on, but there’s a lot of unmet need here. It may be that in the future we’ll only be using PSMA PET to track patients rather than CT and bone scan. But it’s been hard to shift because we don’t still know what that should look like. What should your PSMA PET look like after six months on doublet or triplet therapy for metastatic disease? We don’t have those answers yet.

So let’s go to the first case. So this speaks to a patient who’s getting lutetium PSMA-617 and the question of, why would we do a PET scan during treatment? What kinds of decisions can we make? Because in the VISION study that got the FDA approval for lutetium PSMA, they gave up to six doses once every six weeks. And it wasn’t necessarily based on imaging. But this is one use case for PSMA PET scans in the metastatic setting. So this is actually a published case. It’s not my own patient, but I think it’s very, very instructive. First of all, on the very far left, we see that when the patient has a PSA of 430, their PET scan’s showing a fair amount of disease in the bones and this would meet criteria for treatment with lutetium PSMA provided there’s no disease that’s showing up in soft tissue that we don’t see lighting up on the PSMA PET. So when we’re reading a PSMA PET report, it’s important not only what are we seeing but to make sure we’re not seeing lymph nodes or something in the lung or liver that does not take up that PSMA tracer because we know the treatment won’t go there. With bones, it’s more complicated. Bones can be quiet because they’ve been treated. They don’t always have to take up the PSMA tracer. So this patient has a very nice response to lutetium PSMA infusions. After cycle two, the PSA drops to 15, and after cycle three, the PSA is 3.5. So, this is where sometimes we start to think, well, what does that dramatic change in PSA mean? How much of the cancer has been treated and should we keep administering treatment? So in this case, they saw that the PET scan had essentially become normal and they decided to hold, to not just keep giving the treatment, but to do what’s called adaptive dosing. And nine months later, we see PSA’s back up to 76. And they go ahead and start those last three doses of the treatment. After cycle five, PSA drops to 20. After cycle six, it’s down to 3.4. And again, the scan has cleared. And so this patient received their treatment over a period of 15 months, instead of what would have been 36 weeks, right? Six doses times six weeks. Is this better? We don’t know, right? We don’t have a head-to-head study, although there are active studies asking this question, like RECIPROCAL through the cooperative groups and some studies over at UCLA, for instance. But why would we not want to just march straight through? Well, we know we’re giving that same intravenous dose of radioactivity that’s looking for those spots on the PET scan to land, and the fewer of those spots there are then the radioactivity might land on more normal organs, including the salivary glands. So we know a major side effect of the lutetium PSMA treatment is that these glands are PSMA expressing. And so we get a lot of dry mouth or xerostomia, the smaller the disease that’s been shown, the more the side effects. So this is one of the reasons we’re starting to think about using PET scans as we’re treating to assess how complete has the response been, but this was not how it was done in the main clinical trials. And so we still don’t know if this is right.

Let’s look at the next slide though. I do think this case helps us understand why PSA isn’t enough. So this is another patient with resistant prostate cancer, what we now call APMR, who has actually already had chemotherapy, has sort of a low kidney function and actually has a nephrostomy tube unblocking one of his kidneys. So this makes treatment a little bit more complicated, both for chemo and for lutetium PSMA. But of course, you see on the PET scan, there’s a lot of disease. Even with the PSA starting at 23, there’s a fair amount of disease here that’s lighting up on the PET. So he receives two cycles and actually tolerates them well, we didn’t see kidney damage. We didn’t see increased marrow damage. So we can do it safely even with these compromises in the urinary tract. So should we pause? So in this case, even though the PSA has dropped to 0.29, we see there’s still a fair amount of disease on the right-hand side. So there’s definitely been improvement. I think everyone can see some of the spots have disappeared, but there’s still disease versus that case that dropped to three and it was stone-cold normal, right? Here’s a case where I would definitely say, okay, we’ve made good progress, but we wanna keep going.

On the next slide from Phil Kuo, who is one of my nuclear medicine colleagues at City of Hope, although he has now moved to a different institution. You know, these nuclear medicine radiologists can see a lot more on a scan than the rest of us. And so he did some leveling and sort of shows that the really bright spots are the ones that are gone and there are these lower avidity or lower brightness spots that are the ones that are still there. We don’t know what that means in terms of, you know, will the lutetium PSMA work if we keep going? There’s a lot we need to learn about the radiobiology, why are some spots disappearing and others not? But I think really working in collaboration with our nuclear medicine doctors is helpful when we’re trying to understand how has the PET changed, what does that mean for the patient’s response to treatment.

Phillip Koo, MD [00:32:09]

So this is really interesting, Tanya. You know, the first case shows a patient who responds really, really well. The pictures look great, the PSA responds, and you have these other cases where the response quite isn’t as nice, even though we know from the original pictures that the patient did have disease that had the PSMA receptor. How do you explain that, and what do patients need to know? Because there’s so much hope, and then all of a sudden perhaps it’s not working the way we thought it would work.

Tanya Dorff, MD [00:32:42]

Yeah. I think we are all grappling with that question. You can have two PET scans that look the same at the beginning and get the same treatment and the response is different. You know, just prostate cancer is a different disease in different people. It has different behavior, different biology. So sometimes, you know, your doctor’s going to look at all the information, and that might include, again, things like your genomics, your DNA sequencing from your cancer cells and your germline inherited DNA as well. They might look at something like that. They might look at your initial Gleason score, your PSA, the amount of PSA for the amount of tumor, they might want a new biopsy. There’s a lot of things that we think about and we try to put it into context of what we’ve seen with our patients when we’re saying, you know, I think you might do better with chemo and in this other patient, you might do better with the lutetium PSMA first when we’re kind of trying to decide between our options.

Phillip Koo, MD [00:33:39]

You know, you mentioned genomics, any new findings there regarding, you know, certain genetic drivers, genomic drivers, genetic drivers, that you’re seeing better responses or worse responses with these PSMA-directed therapies?

Tanya Dorff, MD [00:33:55]

It’s so far been mixed, right? There are some reports that certain alterations reduce the likelihood of benefit and others that conflict. So I would say we don’t know yet for sure, but some of us kind of use our gut on that kind of thing. And more data are forthcoming all the time. So the answer might be much more clear in the next six months or a year as more studies report out an association between which genes and the response.

Phillip Koo, MD [00:34:23]

And I think that’s a really important point for all the patients on the line that it is so complicated, and we think we know, but cancer and the human body are just so complex. So let’s go back a little bit. We have patients who are watching who have metastatic disease, who are castration resistant or the new terminology, APMR. They’re being considered to get Pluvicto, but obviously there are other treatment options available as well. You order the PSMA PET, how are the findings on PSMA PET helping you make the decision whether they should get a Pluvicto or maybe they should get something else?

Tanya Dorff, MD [00:35:06]

Yeah, that’s the million-dollar question, so to speak, right? And that’s where the art of medicine comes in. So for sure, we want to confirm that there’s been DNA testing. The next generation sequencing is so important because if we do find a BRCA2 mutation, this is a cancer that may be very, very, very susceptible and have tremendous benefit from a PARP inhibitor and we don’t want to miss that. It’s not that we can’t choose lutetium PSMA or chemo for that patient, but most of us would probably choose that PARP inhibitor first because it’s such a match, such a strong biomarker. If you have this, you really do well from this particular drug. Otherwise, I do look at the intensity of uptake, the number of sites. I think about the patient’s lifestyle, their comorbidities, the urinary tract factors in sometimes. But sometimes it’s how far away does the patient live. Do they have the ability to kind of isolate or at least, you know, use that separate bathroom and those sorts of things for a few days? Sometimes there are patients where that presents an obstacle and we might wanna go a different direction. But the PET scan tells us a lot. It doesn’t tell us everything. And I think a lot of people are working on analyzing PET scan characteristics to help us choose people who will benefit more. But I think when we’re just seeing a tiny amount of progression, sometimes we forget that we don’t have to jump right to our biggest tools, that sometimes we might want to use, you know, immunotherapy with sipuleucel-T, or we might wanna go on a clinical trial with a novel immunotherapy or some other novel approach. We might wanna do focal radiation, right? We have other options. And so I do think trying to assess how much disease is there and how much is it expressing PSMA helps us in deciding when is the right time to choose the lutetium treatment.

Phillip Koo, MD [00:37:00]

Great. So now, you know, we use it to decide whether they get the treatment or not. How are you following these patients? Let’s say they’re scheduled to get six doses. How are you following them during that course of six treatments? And how do you follow them with PSMA PET afterwards?

Tanya Dorff, MD [00:37:17]

Yeah, I think it varies among practices. And maybe Dr. Klaassen or maybe you will want to weigh in. There are people who do it kind of regularly. My approach, if the symptoms go away and PSA is dropping and I know treatment’s working, then I want to use the PET scan at a point where I’m thinking about maybe a pause, maybe adaptive dosing. So I might wait till after the third or fourth treatment. But if after two, I’m not sure, right, PSA hasn’t clearly gone up or down. There’s not clearly an increase or decrease in symptoms, which is very common. Not a lot of patients necessarily have symptoms going in. When I just don’t know is it working, is it not working, then I usually like to do a PET scan after the second cycle. And certainly in the future, as we have other ways of targeting PSMA, like PSMA immunotherapy, we may want to use PET scans at the end to see is there still PSMA expressing disease or has the disease changed and now it’s no longer making PSMA. So also if PSA drops and then rises, there’s different places where that PET scan will answer a question. I think that’s probably like the most general statement one can make is you wanna do the PET scan when it’s gonna answer a question that you have for it.

Phillip Koo, MD [00:38:32]

Great. So, you know, there was a question about the treatment they were talking about, lutetium-177 PSMA-617. So it’s basically a radiopharmaceutical targeted to the cancer cells that are expressing PSMA. So it’s sort of a different type of precision medicine, but it’s really been fabulous for patients and now it’s approved across the whole spectrum of metastatic disease. So very interesting now. Hormone-sensitive patients now have the option, and there was a question about when do you add this to doublet treatments in metastatic disease? So what’s sort of your approach and thoughts there?

Tanya Dorff, MD [00:39:14]

Yes. That’s a super complicated one. I think we do have to consider toxicity and the fact that earlier in a patient journey, there may be many, many years of life. That’s what we hope and expect actually from newly diagnosed metastatic prostate cancer. And we don’t yet know what lutetium PSMA infusions might cause down the road, you know, five to 10 years. We have, you know, two-year, three-year, we have some follow-up, but I think there’s gotta be a real conversation as we move it earlier about what dose is appropriate, how many doses, what could be the risks that we don’t yet have answers for, and the fact that it still works really, really well later on. Not that we wanna keep treatments in our back pocket, we know that intensified therapy is better. But there’s such a thing maybe as too much intensification. Certainly, I think not everyone needs it right up front.

Phillip Koo, MD [00:40:21]

You know, I think that’s a great point about safety, and there are a lot of questions being asked about the safety of getting serial PSMA PETs. I think I’d like to put it in context. The therapeutic dose that you’re getting with the lutetium-177 is magnitudes higher in terms of radiation exposure compared to a PSMA PET. So the amount of radiation you get with a PSMA PET, even if you get it every six months or a year, is still only going to be a fraction. That being said, you know, you have metastatic prostate cancer and the risks of that do not outweigh the benefits. So the benefits outweigh the risks and that’s why you’re getting the PSMA PETs perhaps a little bit more frequently. So, you know, Dr. Dorff, you had a case about some of the adverse events potentially with lutetium-177 and you talked a little about that patient with the renal catheter and I think you have a slide. Becky, if we could bring it up, and this is something for patients to be, you know, thoughtful about, because renal disease and renal damage is something we’re learning more about with some of these treatments, and it’s great, because PSMA PET and these imaging tools really give us a lot of different information. So can you walk us through this case?

Tanya Dorff, MD [00:41:37]

Yeah. So there are a lot of patients with prostate cancer who have obstruction in their urinary tract. And some people who have had long-term obstruction or have other health issues like diabetes or high blood pressure where their kidney function is impacted. And although the VISION trial, the registrational trial had patients with a requirement of a certain kidney function, in reality, we sometimes do use it at lower function, like in the earlier case. And then in this case, as we saw the cancer on the left, this lymph node on that top left image, when you look across to the top right, that lymph node is blocking the kidney on that side. So when we infuse the lutetium PSMA, it gets excreted in the urine. And so we won’t give an infusion unless we unblock this kidney, because we know that then the treatment’s not getting excreted and there’s a concern that it could hurt the kidney and or linger longer in the body and suppress the bone marrow more. So one thing I wanted to highlight was if you look below on the right, you can do a SPECT scan and Phil can talk more about the difference between SPECT and PET, perhaps, if of interest, but this image is the treatment and this showed that because we had unblocked the kidney prior to treatment, we had put in a stent so that the urine could flow out of that kidney, the treatment is not lingering in that kidney and indeed this patient had safe treatment, although he did have, you know, issues with urosepsis, which is always an issue potentially when we’re having surgical interventions and instrumentation, and then also unfortunately had some radiation cystitis and clot retention. And so we had to weigh continuing this treatment versus these like major side effects. So we have to treat a whole patient and it requires really multidisciplinary coordination between the urologist, the nuclear medicine team and medical oncology.

Phillip Koo, MD [00:43:48]

Great, thank you. So, all right, we have some time just to go over some of the questions that have been submitted. Zach, there have been some concerns about PSMA not being a great biomarker test. Can you talk a little bit about PSA with prostate cancer? When do you know certain tumors are not PSA expressing and how do we know that PSA is a good trigger to get PSMA, maybe is that too late sometimes?

Zachary Klaassen, MD [00:44:21]

Yeah, it’s a great question. I don’t think there’s an easy answer, Phil. I think generally the majority of even high-risk prostate cancer localized or even locally advanced is going to be PSMA expressing and PSA producing. As we get into further lines of therapy, certainly a little more to Dr. Dorff’s wheelhouse in terms of advanced disease, second, third line treatment, these treatments may cause the tumor to sort of shift and not produce PSA, but still continue to progress. One of those types of cancer is called neuroendocrine. And certainly in those situations, PSMA PET may not be the ideal imaging modality. But I think the take home for me, at least in my opinion, is that early on, even with high-risk disease, locally advanced, even early metastatic disease, PSMA is for the most part, for most patients, gonna be expressed and PSA will be produced.

Tanya Dorff, MD [00:45:19]

Yeah, just to dive in a little bit more on that. We have to separate two different scenarios, right? When we have not given hormone therapy, when we’re not metastatic and we just have rising PSA, doing the PET scan, you know, according to PSA is helpful because we know there’s sensitivity threshold in that defined scenario. When, on the other hand, we have a metastatic patient who we’re treating, the rules look a little bit different. But we know some cancers can start to grow without PSA in that setting, and they may not be picked up on a PSMA PET. So it may be that regular scans are used. But when we’re not on treatment, again, the PSA is a really, really good marker that helps us understand well before we can typically see it, whether there is any cancer.

Phillip Koo, MD [00:46:20]

Alright, there were some questions about PSMA PET, this is my opinion, but if resources were unlimited and money was endless, my personal take would be yes, PSMA PET would be used all across the board, but we’re not there yet, hopefully over time the costs come down and maybe the utilization will continue to decrease, but that’s not for today. Dr. Dorff, we often follow patients, we talked about PSMA PET for patients with advanced disease who are getting various treatments. Oftentimes if the patient gets a lot better, that’s great. If the disease gets a lot worse, it’s not great, but the answer is very clear, you have to change treatments. What do you do when you sort of have that mixed response where some lesions might be getting better, some are getting worse? How do you handle that scenario?

Tanya Dorff, MD [00:47:10]

Yeah, that’s one of the reasons that we’re not yet ready to roll out using PSMA PETs during treatment for advanced disease, because we haven’t yet defined how should things look and what does that mean for benefit from treatment and survival. So if we’re starting a new treatment, especially in the resistance setting, outside of lutetium PSMA where it really kind of matches with the PET scan, when we’re starting a different kind of a treatment, we don’t know whether there can be flare, right? Things can look a little brighter because we’re actively killing cancer in that area and so we’re seeing more of it. And so we know that happens with bone scans, right, that the bone scan can look worse even though the person is clearly getting better because of the remodeling flare on that type of imaging. So if everything’s in the same position on the PET scan and some spots get worse and some spots get better, you know, as always, we look to other things about the patient to help guide us in our decision making. We look at what is the PSA doing, and also maybe some other labs like alkaline phosphatase that helps inform us about bone, or maybe their blood counts, and we look at how the patient’s doing, right? So if I’m seeing a report that says some spots got better, some spots got worse, there’s no new spots, and the patient is feeling loads better, and or the PSA’s down and the other labs look good, you have to treat the person and not the scan, so you would probably continue, but it becomes complex because the reports can just have so much detail about what’s increasing, what’s decreasing and what’s meaningful. When SUV goes from 5.4 to 6.1, is that meaningful? We still have some work to do to define that, and so we really need to look at the whole picture as long as there’s not new disease, as long as the patient’s feeling good, as long as the labs are looking good, we just kind of scratch our heads and wait for that next scan and the next set of data.

Phillip Koo, MD [00:49:14]

And, you know, I think that you put it great and there’s still so many questions that need to be answered. And then that’s where research will continue to drive this forward. There are some questions about actinium. There are a few trials that are now open using actinium PSMA. So if you’re interested, they’re open and available. I think there might be three or four different trials. Actinium, very promising. So we’re gonna bring this to a close and Zach, I’ll start with you and then go to Tanya. You know, Zach, you’re a urologic oncologist. Your goal is to try to cure patients through surgery. What has PSMA PET meant to your practice? And what benefits have you seen, just anecdotally, to the patients that you treat every day?

Zachary Klaassen, MD [00:49:58]

Yeah, great question, Phil. Always good to be with you guys. I tried to answer as many questions on the chat as I could. I apologize if I didn’t get to everybody. What PSMA PET has done from a surgical standpoint is put into a little tighter box who we should offer surgery to, mostly because the side effect profile of surgery is still pretty significant. Urinary incontinence, erectile dysfunction, the two main ones, and really sort of aligning that risk-benefit ratio, the benefit of a surgery, the risk of the side effects, and trying to get a cure based on that whole conversation. So it’s probably made, I mean, Gleason 6, let’s just say it should be active surveillance, the 3 plus 4, the 4 plus 3 is a few, 4 plus 4 is the odd 4 plus 5, with a negative PET scan still can benefit from surgery, but it’s possibly taken out some of those high-risk patients that we may have operated on that we no longer operate on because the PSMA PETs show something. The last thing a surgeon and a patient wants is the surgery to be done, the first PSA is 0.4, 0.35. We call that a PSA persistence. That is a very difficult discussion. It’s very frustrating for the patient and for us because clearly there’s something there that we weren’t able to get out surgically. And then we’re thinking about adjuvant radiotherapy after that. So it’s kind of tightened up that box of who I think should be getting surgery and who could benefit from all of it.

Phillip Koo, MD [00:51:26]

I love that, so you’re being able to pick the right patients for surgery better. Anecdotally, are you seeing less of those cases of PSA persistence?

Zachary Klaassen, MD [00:51:36]

I think so. I think, you know, I think because even like, say, pre-PSMA PET, Gleason 4 plus 5, already thinking this is going to be multimodal therapy. And there’s still some people that do think that surgery and then radiation in that setting is best. I think the data is probably a little anecdotal there. But from my practice, knowing what the side effects of surgery are, I’ve noticed less PSA persistences because we’re doing what I think is more appropriate prostatectomies.

Phillip Koo, MD [00:52:05]

Great, I think that’s perfect and that’s a huge plus for patients thanks to this tool. So Tanya, you’re a medical oncologist, you treat patients who have advanced disease, obviously very different, cure is not sort of the goal there. How has PSMA impacted your practice and what benefits have you seen?

Tanya Dorff, MD [00:52:25]

Yeah, so the biggest way is in selecting patients for this new, or not so new anymore, but lutetium PSMA-617 treatment, right? We have to have PET scans to determine if someone’s a good candidate for that treatment or not. So that’s a huge impact, and we don’t have to fight quite as hard anymore to get PET scans because it’s now understood that if we’re going to use this treatment to help our patients do better, we need to first scan them. But it creates so many questions, right, of when we have these mixed changes or when we have an equivocal finding, like is this patient really metastatic or is this a false positive? So it’s created a lot of need for close scrutiny and close collaboration with our radiologists. So, I worry, you know, our reports go straight to our patients and they see things and they worry. They think that the uptake that’s seen in the pancreas that’s normal might actually mean there’s cancer in the pancreas. So I really encourage patients to look at their PET scan, but really talk to their doctor about their PET scans and what it means and what the limitations are because they’re very helpful, but they are complex.

Phillip Koo, MD [00:53:48]

That’s great, I think those are really, that’s a great summary. Here at PCF we’ve been very fortunate to receive a lot of donations which we’ve been able to fund in the past couple years several studies that are looking at the radiation biology. Why are some patients responding, why are some people not responding, and I think we’re very hopeful that in a year or a couple years we see the information that can then help us pick the right patients for these treatments. So thank you all for your generosity in allowing this type of research to occur, which as you can all see, these are questions that our physicians deal with every day. So thank you all for being here and we’ll see you all in a couple of weeks. Thank you.