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Neal Shore: Well, hi, everybody. Neal Shore here with you today at Carolina Urologic Research Center. It's a great pleasure to be joined by my good friend and colleague, Zach Klaassen, who is with Georgia Cancer, and really does some of the pioneering work in research and education, as well as he's a prominent uro-oncologist with a busy clinical practice. This is all part of our discussions highlighting the state-of-the-art, interdisciplinary management of prostate cancer. Dr. Klaassen is going to present a case study, and really what it's going to focus on is the new PSMA PET imaging in high-risk localized cancer. And how are we employing this? How are we implementing this in the real world, appropriate for both tertiary academic centers and community practices? So thanks very much, Dr. Klaassen.

Zach Klaassen: Neal, thanks so much for the kind introduction. Always good to chat about prostate cancer with you as well. So basically today, as Dr. Shore mentioned, we're going to talk about a case study from a patient in my practice and where the use of molecular imaging really helped this patient. So we'll go through the case study and then Neal and I will have a conversation at the end.

So this patient is a 67-year-old, African-American gentleman. I saw him as a second opinion for consideration of robotic prostatectomy with pelvic lymph node dissection for Gleason 5 + 4 disease, 6/12 cores were positive, all on the left side. This was done at an outside institution. And his initial PSA was 14.3. So prior to the consultation, he had received conventional imaging with a CT and a bone scan, and these were both negative. And at the time of the consultation in November of 2023, he was very interested in surgery, healthy gentleman. So the question is, what do we do next?

So I'd like to just deviate from the case for a minute to talk about the OSPREY trial. And this was a trial published in the Journal of Urology by Ken Pienta and colleagues in 2021. And this really was the key trial for DCFPyL in the staging of men with prostate cancer. So this was evaluating DCFPyL in men diagnosed with metastatic prostate cancer compared to the histopathological gold standard. And so, to get into this study, they had to have a baseline bone scan or CT that was negative or equivocal.

Jumping right to the main results of this trial, we see on the left the sensitivity, specificity, positive predictive value, negative predictive value, looking at lymph node positivity. And this is again the gold standard of histopathology. So we see excellent negative predictive value in yellow, excellent positive predictive value in red, and a very good specificity at 97.9% in light blue. We do see a bit of a lower sensitivity, and this is all pelvic lymph nodes. So when they did a post hoc analysis increasing the pelvic lymph node diameter to greater than 5 millimeters, the sensitivity did improve up to 60%.

Here we see the sensitivity and positive predictive value across all PSA ranges. And you can see, as expected, high PSAs, excellent positive predictive value and sensitivity. As we move towards the lower PSAs, we still see a very good sensitivity and even at a PSA less than 0.2, a sensitivity of 50% and positive predictive value of 67%. So the take-home message here obviously is with a higher PSA, increasing sensitivity and positive predictive value.

So back to the case. This patient did have a DCFPyL PSMA PET on December 13th of last year, and these are some representative images. As we would expect, there was intense PSMA uptake in the prostate gland as highlighted here, SUVmax of 19.9. And then we also see in a couple of different cuts, PSMA uptake in the left pelvic lymph nodes, SUVmax of 3.8. And then moving up a little bit higher, looking at some of the bone lesions, we see an S3 vertebral lesion, a left iliac crest lesion on the left, and we also see a T5 vertebral lesion, SUVmax of 3.4. So clearly, this patient has multifocal metastatic disease based on his PSMA PET scan.

So this is where the multidisciplinary treatment plan really does come into play after this imaging. So I tend to say that this patient was saved from a robotic prostatectomy. This would've been a patient that would've had a PSA persistence after surgery. And there's nothing more frustrating as a surgeon than sitting down with a patient after surgery and that first PSA is greater than 0.01. When we get these images, it really does come into a multidisciplinary discussion. So this patient was seen by both medical oncology and radiation oncology. There was a discussion around triplet therapy with ADT + darolutamide + docetaxel. The patient ultimately opted for doublet therapy with ADT + enzalutamide, and because of his relatively low-volume metastatic disease, he did receive radiotherapy to the primary gland based on the STAMPEDE Arm H data.

So just to conclude this case, certainly in my opinion, PSMA PET/CT imaging has revolutionized the staging of high-risk localized prostate cancer. And I think it's important to point out for our listeners that although long-term follow-up is required to assess the impact of changes in management in terms of long-term oncological outcomes, patients and physicians do have the confidence at that next visit after the imaging that they have appropriate treatment care plans. And I think this does help with a lot of the anxiety that goes along with appropriate treatments, knowing that they have the best imaging possible to help guide care at that visit. And as an optimist, I think that as we follow these patients long-term, we hopefully will see improved oncological outcomes. And so this does highlight multidisciplinary care as being of the utmost importance for high-risk localized disease. And this may actually be metastatic hormone-sensitive with molecular imaging. And so I think it's important to emphasize that based on the NCCN guidelines, anybody with unfavorable intermediate and higher-risk disease are all candidates for staging with a PSMA PET scan.

Neal Shore: Well, that's such a great case because we all see this patient.

Zach Klaassen: Yeah.

Neal Shore: And historically, if he'd gone to prostatectomy, the meta-analysis, say 20 to 50% BCR.

Zach Klaassen: Yeah.

Neal Shore: And he went even to primary radiation with ADT 18 months to 36 months, depending upon how you look at that, 20 to 50% likelihood of a BCR once he returned to eugonadal testosterone levels, so trying to optimize that therapy. But what's so interesting to me is, and I'd love to hear your thoughts on this, Zach, is all of our approved therapies, our oral and parenteral therapies, have been based on PCWG3 and RECIST criteria, which really is conventional imaging, as you said, CT scan and technetium bone scan. And then at least in the US in 2021, we saw these approvals. And now we have two fluorinated 18F PSMA PET. We have a gallium PSMA PET. And so we now suddenly went from kind of nothing to a lot of different options, but our classification is based, as I said, on these PCWG3 and RECIST.

So we think about low-volume, high-volume tip or even look at some of the work that was done by Karim Fizazi, high-risk, low-risk, all based on conventional imaging. And now we're still sort of debating. This fella, one could argue, is now with a new separate classification, negative CT scan, negative bone scan, but yet it looked like there was what, at least three bone lesions, some soft tissue disease, and you had the MDT talk about triplet therapy versus couplet therapy, holding off on surgery, thinking about radiation based upon STAMPEDE Arm H. So it's so fascinating. How do we further teach our colleagues? And what are some of your thoughts about this new need to reclassify?

Zach Klaassen: Yeah, great points, Neal. I'll use the example of the non-metastatic CRPC data, which is all based on conventional imaging. We have three trials, very similar entrance criteria, very similar MFS OS benefit. And if you look at the study from Fendler and colleagues in 2021, I believe, 96% of patients that fit that criteria all have PSMA-positive lesions. So I look at those patients and I think, is there a criterion of ultra low-volume PSMA-positive metastatic disease? Certainly, this is not in the literature, but it's getting to the point of we have a patient that would've been historically high-risk localized that we just talked about. Now he's PSMA PET-positive, metastatic hormone-sensitive. And so we see it in that criterion. We see it in the non-metastatic CRPC.

I think we really have to think about how we discuss this with our patients, how we teach our residents, how we teach our colleagues, because the data that we have, which is all excellent phase III RCT data, has to be interpreted now with the context of PSMA PET. I don't think there's a good answer for it. I think we know those medications work. And I think if you look at the mnCRPC data, even with low-volume PSMA PET-positive disease, those patients do well with ADT + either enzalutamide or apalutamide or darolutamide. So it's a very good question that I don't think we have answers for, and it's kind of in these discussions and our clinical judgment to sort of interpret it.

Neal Shore: Yeah, I fully agree. And it's very interesting in different parts of the world, where there's easy accessibility to PSMA PET but still not everywhere. And so wouldn't it be great to do the appropriately designed study to see the clinical utility?

Zach Klaassen: Yes.

Neal Shore: There's no doubt there's clinical utility.

Zach Klaassen: Yeah.

Neal Shore: We may debate from a radiation oncology or surgical oncology perspective, medical oncology, systemic therapy approach, or even SBRT approach. And that's where we're starting to see a lot of folks acting without necessary level-one evidence. But I get it. When you're sitting knee-to-knee in the clinic, the patient says, "Well, what do I do short of not being in a clinical trial?"

Zach Klaassen: Right.

Neal Shore: Which, of course, I think you and I would both agree if there's a good clinical trial to sort of give us a better answer here. Let me ask you this question, Zach. What about your experience with the interpretation of scans? It's been talked about there's a learning curve amongst our radiologists, our nuc/med radiologists, to really become better at interpreting these scans and how to really incorporate into the report the SUV background, SUV for the liver, false positives. Specifically, some traumatic rib lesions oftentimes show up as false positives on scans. So how are you seeing that evolve?

Zach Klaassen: Yeah, I think being at an academic medical center with two excellent, very well-versed readers, I think I'm a little spoiled, much like some of our other colleagues that may be at high-volume centers. But generally, you're right. I mean, if you go into the community, maybe they're looking at a scan every month or every other month, and they've had experience maybe with axumin. But I think the one thing I would say is that specifically with Pylarify or DCFPyL, there is Pylarify AI, which is a software program that could help maybe some of these smaller community hospitals or lower-volume PSMA PET imaging centers.

And I think it's all about putting into context. You're right, there's still going to be false positives. And I think just like we do with CT and bone scan, you put that image into the context of Gleason Score, PSA, all the things that we're used to doing. I think that doesn't go out the window. I think when I looked at this patient's scan, 5 + 4, PSA is 14, multiple areas, you have to believe that those are real. And really when you get that SUVmax really lighting up, I think that truly is important for the report to have those SUVmaxes because I think that does lend some credence to maybe interpreting is this truly positive or not?

Neal Shore: Yeah, I know. I 100% agree with you. That's why this is such an important case. It's very illustrative. There's no doubt about it. I really like the notion about these AI algorithms. This really perfectly lends itself to that, that deep machine learning, to really say aha, this is significant as opposed to not, and how can it change and impact clinical utility. So really great points. Thank you so much for sharing the case. Your insights on this, to me at least, I wonder how you feel about it, I find right now that my greatest utility is in high-risk localized prostate cancer patients, grade groups 3, 4s, and 5s, inclusive of their PSAs, inclusive of the DRE, maybe also if they've had an MRI of the prostate. But then also the whole other topic is the BCR patients.

Zach Klaassen: Yes, absolutely.

Neal Shore: Much like the nmCRPC in that Fendler paper you quoted, which I think is a great paper, we know that our BCR patients who are negative on conventional imaging like in EMBARK, but then you get a PSMA PET and there's a very high percentage that are going to show up with a lesion.

Zach Klaassen: Yeah, I totally agree, Neal. I think one thing we didn't touch on, too, but just food for thought is what if this guy's PSMA PET was negative and you operate on this guy, right? And I think that's always a challenge, too, because we have good literature for radiotherapy + ADT + abiraterone potentially for these patients with high-risk disease that have negative imaging. And I think that's where the clinical trial aspect really comes in. Taking a patient that we just presented negative PSMA PET, what do we do next? And I think that's really, really difficult because we have all the same studies, again based on conventional imaging, too. So I think, again, it's a phenomenal tool in the context of the clinical situation, just like we've been doing with bone scans and CT scans.

Neal Shore: Yeah, you make a great point. Exactly. Because not everybody has PSMA avidity.

Zach Klaassen: Right.

Neal Shore: We've seen that in CRPC studies, and we're going to see more of that in larger series with high-risk localized. You're absolutely right. And then, of course, we're doing some additional neoadjuvant adjuvant trials to try to have patients do better with their primary interventional therapy. And there's some exciting data that I think is going to come forward, some at AUA this year and at the end of the year. So a lot of great things to look forward to. Final thought, Zach?

Zach Klaassen: Yeah, I think the challenge, especially in the staging, I think, is still getting insurance approval. It's a little bit easier in the biochemical recurrent population. I typically have my APPs when they do the peer-to-peers in these situations of high-risk staging just quote the NCCN guidelines. You do not need a negative bone scan or CT scan to get the PSMA PET ordered. And oftentimes that works. You have to push through. But certainly, these patients that come as a second opinion with negative CT and bone scan, certainly before I do anything, these patients are getting a PSMA PET because I truly think when we see this data over the next 5 to 10 years, getting that right treatment plan right off the bat, and this is an obvious case, for sure, but in the less obvious cases, hopefully, we're seeing improved oncological outcomes.

Neal Shore: Yeah. Great. That's a great shout out about it. In NCCN, they've incorporated it, and also it's part of EANM and SNMMI and we all have that. The bane of our sometimes daily existence is having to fight these pre-authorization things, but we're doing it for the best interest of patients. So that's a great shout out. Zach, thank you so much. This was a great case and with great insights. Really appreciate it.

Zach Klaassen: Always great chatting with you, Neal. Thanks so much.