Phillip Koo: Hello, welcome to UroToday for a special session, where we are going to review the indications for PSMA PET in patients with prostate cancer. My name is Philip Koo and I'll be serving as a moderator for today, and I am joined by an esteemed group of colleagues who really need no introduction. First, we have Dr. Oliver Sartor from Tulane University and Dr. Neal Shore from the Carolina Research Institute.

Just to sort of kick things off, I'm going to first start off by reviewing the indications. As we are all aware, PSMA PET was approved by the FDA in the USA in December 2020 for PSMA 11. And that was followed by the approval of PYLARIFY, which is an F 18-based PSMA agent, in May 2021. Both of these agents pretty much have identical indications. They're indicated for use in men with prostate cancer, and the first indication is for patients with suspected metastasis who are candidates for initial definitive therapy, and then the second indication is for patients with suspected recurrence based on elevated serum PSA levels. And again, these are pretty much identical for both of these agents. First, we'll start off with a discussion about patients with suspected metastasis who are candidates for initial definitive therapy. I'll turn it over to Dr. Shore, and Neal, wanted to hear your thoughts about how you use this in this category of patients.

Neal Shore: Thank you so much, Phil. Great to be here with you and Oliver, as always. As we say, these indications and approvals for gallium PSMA and 18 FPyl PSMA PETs, it is not short of the ability to say these are game-changing imaging technologies, and in large part, thanks to the nuclear medicine, radiology experts such as you and your colleagues.

So now that we have these approvals by FDA for two distinct different PSMA PETs, I really enjoy using this for my patients who have high-risk localized prostate cancer. And of course, there's a spectrum of how we tend to define that based upon DRE, based upon histopathology, but really nice work done by Mike Morris and others, looking at Ken Pienta and the OSPREY and the CONDOR trials, has demonstrated that it can affect clinical utility and decision making based upon the new findings, the greater accuracy that we see in PSMA PET scanning. Do you continue forward with a localized, active intervention surgical extra patient prostatectomy or radiation? Or do you add systemic therapy? Or do you just use ADT? Do you change the field of your radiation? And these are the types of things that are being addressed, and they're still controversies, but I think it just adds to our ability to make a better-informed decision with patients and their families.

Phillip Koo: Thank you. Oliver, your thoughts?

Oliver Sartor: I'm going to go back to this suspected metastasis who are candidates for initial definitive therapy. That's really broadly stated, and it didn't give us precise guidelines, which I think leaves the physician as the ultimate decider. Now, this is going to interplay with the insurance companies, and I think, as we go forward, there'll be some guidelines sets. So who might have a suspected metastasis? You know who's a candidate for definitive therapy. Typically that's radiation or surgery, with radiation, either external beam or brachy. And these candidates, if they're in the higher risk of the spectrum, say Gleason 8 to 10, PSMA more than 20, T3 disease on your DRE, I think that's a pretty clear indication.

I think where things get a little muddier is in that intermediate-risk patient. And we now sort of subdivide the intermediate-risk patients into favorable and unfavorable. And I think for the unfavorable, I'm doing it in my practice, I'll say, and those are the 4 + 3 or if they have more than 50% of their biopsies involved with tumor or they have two out of the three risk factors, PSA more than 10 and the Gleason 7 and a DRE that may show bilateral involvement. So the more risk factors you have, whether it be PSA, DRE, or Gleason score, and particularly the 4 + 3 that have more than 50% of their grand involved with the biopsies. Those are candidates that I think are very appropriate.

Now, as we go forward, I think there's going to be some, perhaps, more definitive guidelines that develop under the insurance regulators who really determine who's going to get paid for and who's not going to get paid for, but that's sort of where we are now. And I think there's a lot of latitude. The bottom line is, physicians, right now, can kind of create candidates for initial definitive therapy with suspected metastases with no clear absolute guidelines over who that is. But high-risk, high intermediate-risk, I think that's where the money is.

Phillip Koo: Great discussion. I agree. I think a huge step forward, being able to have a label or an indication that considers it for use at initial diagnosis before definitive therapy really opened up a whole slew of potential uses and I think we'll learn more about this in the future. So the second indication is with suspected recurrence based on elevated PSA levels. I think, oftentimes, we've looked at this very narrowly just thinking initial biochemical recurrence, but clearly this is broader than that. So, Dr. Sartor, maybe we'll start with you and hear your thoughts about this indication.

Oliver Sartor: Sure. I've also interpreted this relatively broadly, Phil. The clear indications would be post radical prostatectomy, post radiation, PSA rise. But it doesn't really specify that it has to be the individual who's coming out of initial radiation or initial surgery. What about the individual may have had a recurrence after hormonal therapy? And you can see for the wording with suspected recurrence based on elevated PSA, well, that could be appropriate too, right? And by the way, there's some individuals who might have the emerging castrate-resistance, particularly the nonmetastatic castrate-resistant, it may in fact be very appropriate to have scanning done and maybe metastasis director therapy. So there's a lot of latitude here.

Also, is there a PSA cutoff? I'll simply say, if you look at the really nice studies published from multiple centers, if it's below 0.2 for a radical prostatectomy and the probability of finding something's pretty low, I'm generally pushing the PSA to about a 0.5 ish or so. I'd like to hear from Neal on this. And then for the radiation, do we endorse the nadir + 2, which is Phoenix definition of postradiation recurrence. But I'll simply say that again. There's a lot of latitude. Radiation surgery recurrences, hormonal recurrences, and maybe even more. So, I'm thinking about this in broad ways, not narrow ways. I don't know. I'd love to hear from Neal.

Neal Shore: Well, I would agree with everything you said there, Oliver. It was a great summary. A key point is, as you stated, this is not just for the classic BCR, biochemical relapse, post-RP, post-RT. It's for really any rise in PSA. Now, we need more data to understand the ultimate clinical utility for it. But for me in my practice, I'm using it regularly now for your traditional BCR patients.

Oliver Sartor: As you say, there are going to be other indications in PSA rises in the CRPC population. How to best utilize that is important. What this indication and the use of PSMA PET is really standing on its ear now, are use of conventional imaging, or what we call CT scan and technetium bone scan, because all of our therapeutics have been based on conventional imaging. And now that we have more sensitive, more accurate ability with the PSMA PET, how will it inform us in terms of therapeutic decision making, whether it's, as you state, metastasis-directed therapy versus systemic therapy or a combination of both of those modalities? So the trial opportunities are really, really important right now for us to get the level one evidence required.

Neal, let me throw in one more issue that brings the PSMA imaging to the floor, and that is the impending approval of the PSMA lutetium-177, which will almost certain be inclusive of those individuals identified in the VISION trial who have PSMA PET-positive metastatic disease. And that's going to be a whole other issue. But I just want to raise it to make people aware that PSMA lutetium is coming, and it's coming pretty soon.

Phillip Koo: Yeah.

Neal Shore: Yeah, that's right. And thanks to your leadership on that. And then the question will be is, do you have to get a baseline PSMA PET in order to qualify for lutetium PSMA theranostic? How will PSMA PET be used to follow these patients for additional cycles and/or investigation for resistance? So these are really important issues that need to be clarified

Phillip Koo: Well, great. Well, thank you both for your input. I think great discussion. And just to summarize, clearly there's a lot of latitude with regards to the use of PSMA PET in patients with prostate cancer. Clearly there's a broad range of use pre-definitive therapy, and also a lot of uses in patients who have elevated PSA following definitive therapy. But definitely a lot of opportunities to get more data and have a better understanding of the impacts of how this impacts management. So we really appreciate your time and keys here and look forward to actually having that discussion about lutetium-177 PSMA once it's approved.

Oliver Sartor: Thank you, Phil. Thank you, Neal

Neal Shore: Thanks, Phil.