Navigating the Landscape of FDA-Approved PSMA Diagnostics: Pros and Cons - Delphine Chen

June 14, 2024

Delphine Chen discusses the evolving landscape of PSMA diagnostics and therapies for prostate cancer with Phillip Koo. Dr. Chen outlines the use and performance of key PSMA imaging agents: Gallium-68 PSMA-11, and the F-18 agents PYLARIFY and POSLUMA. She explains how Gallium-68 PSMA-11, traditionally paired with Lutetium-177 PSMA, is effective but newer F-18 agents offer higher signal-to-noise ratios. Despite similar diagnostic performance across these agents, nuances like bladder activity and sensitivity levels vary. Dr. Chen emphasizes the importance of standardizing imaging techniques to ensure accurate, consistent results in clinical practice. She also touches on the role of FDG PET scans, highlighting their use as prognostic tools to complement PSMA PET in patient selection and treatment planning. This nuanced approach enables more precise and informed decision-making in managing prostate cancer, enhancing the potential for personalized patient care.


Delphine Chen, MD, Professor, Wil B. Nelp, MD, Endowed Professorship in Nuclear Medicine, Director of Molecular Imaging, Fred Hutchinson Cancer Center, Seattle, WA

Phillip J. Koo, MD, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, AZ

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Phillip Koo: Hi, I'm Phillip Koo, and welcome back to UroToday. Here at ASCO 2024, Dr. Delphine Chen, who's Director of Molecular Imaging and Therapy at the Fred Hutch Cancer Center in Washington, gave a presentation updating the audience on the current status of PSMA diagnostics and therapies. Thank you for joining us.

Delphine Chen: Yeah. Thank you for the invitation. I'm happy to... Yeah, it's an exciting topic for nuclear medicine right now, so...

Phillip Koo: I agree. I think it's wonderful that nuclear medicine can play such a large role in patients with prostate cancer. We've really experienced almost an embarrassment of riches when it comes to PSMA diagnostics, and now there are, what, three or four FDA-approved products out there.

Delphine Chen: Yeah.

Phillip Koo: Can you give us a quick overview of the various imaging agents, and maybe some quick pros and cons of each?

Delphine Chen: Sure, absolutely. So the very first was Gallium-68 PSMA, which has been probably the most widely used around the world, and that was approved in 2020, and then we have two F-18 agents, the F-18-DCFPyL, or PYLARIFY, and then what was called rhPSMA-7.3, or now POSLUMA, and in terms of how they perform, Gallium-68 PSMA was traditionally used in concert with Lutetium-177 PSMA, so when you look at those trials and you look at the structures of those compounds, the Gallium-68 PSMA-11 looks more closely like the PSMA-617 that's used for therapy.

In terms of the F-18 agents, they both have much higher uptake levels, and so you see very high signal-to-noise ratio. Similarly, you do see high signal-to-noise ratio with the Gallium-68 PSMA agents also, but it seems to be just even more intense with both of the F-18 agents.

In terms of their diagnostic performance, when you look at all the clinical trials, both in initial staging and biochemical recurrence, the numbers are fairly similar. There are small differences in sensitivity, so when you look at the detection of pelvic nodal metastases in initial staging, it's a little bit lower with the rhPSMA-7.3 based on the data they published, but the others also are low, in the 40% range, but all three have very high specificity, so if you see uptake, it's almost certainly a prostate cancer metastasis in the appropriate location.

Phillip Koo: So there's been lots of discussion about biodistribution, bladder activity, X, Y, Z. What are your thoughts on some of that discussion that's occurring, particularly around bladder activity?

Delphine Chen: Yeah, yeah. I know the data published with the rhPSMA-7.3 POSLUMA agent showed that there's very little bladder activity, which would lead to lower technical artifacts that should improve your ability to see nodal metastases in the pelvis, and so that's why it was interesting that that study still showed a lower sensitivity, but I think in real-world practice these agents always perform a little differently because all the clinical trials have relatively strict eligibility criteria, so I think we need to see how that performs, and I think it'll be helpful for medical centers with higher volumes to actually publish their clinical experience with the tracer. But certainly, I would expect at least fewer technical artifacts, just based on the data that's been published so far.

Phillip Koo: I think that's a good reminder to everyone not to compare trial to trial just because again, the designs are going to be different, a lot of things will be different.

So you brought up an interesting point about using PSMA PET as the test before you start therapy, and Gallium-68 PSMA-11 was the one used in the trials, but that when it first came out it was controversial. There were questions of whether you needed a Gallium-68 PSMA-11 or if you could use any PSMA PET agent.

Delphine Chen: Yeah, yeah.

Phillip Koo: So where are we with that and what are your thoughts on this?

Delphine Chen: Yeah, so I know the Society of Nuclear Medicine and Molecular Imaging came out with a statement when the DCFPyL, or PYLARIFY, was approved, saying that you could use either agent to use for treatment selection for Lutetium PSMA. The indications are within the Gallium-68 PSMA, so all the Gallium-68 PSMA approvals, which were based on the UCLA-UCSF NDA filing, plus the drugs by Telix and Novartis, they all include that, and especially the latter two, and they include that expanded indication of selecting for Lutetium PSMA.

I think in terms of identifying PSMA expressing disease, I agree with what the Society says. We can see if we have highly PSMA expressing disease that warrants treatment with Lutetium PSMA. I think the challenge is going to come in the quantification because all the quantitative data we have so far is with Gallium-68 PSMA, and using that to select with Lutetium PSMA, so the cutoffs used in the TheraP trial, which was probably the most robust data we have in terms of using imaging biomarkers for therapy selection, they used a maximum SUV of 20, and then a minimum maximum SUV of 10 in all lesions, and the SUVs we know from the F-18 agents are going to be different. They're all going to be higher than what we see in PSMA.

And then if we're going to start using PET for predicting dosimetry, we'll have to look at that even more carefully, and so... We were talking about this earlier, and I agree with yours and others in the field saying, "We're going to have to redo the quantification or..." maybe not redo, but really look at what the quantification is of the F-18 to predict dosimetry when we're starting to get into that space.

Phillip Koo: Yeah, I agree with you a hundred percent. We need to raise the bar, the fidelity and, to me, of how we design the trials and study, this needs to be at a higher level.

It always concerns me when we talk so much about SUV, which... It could be variable based on cameras, reconstruction techniques, and all this, yet we... I guess it's just human nature. We love to fixate on a number and have a very concrete threshold.

Delphine Chen: Yeah, yeah, and I think through SNMMI and other efforts, they are trying to... All clinical trials that use PET will use a phantom study to qualify that scanner, to make sure it's within certain parameters so that the quantification from that particular center and that particular scanner can be compared to other centers. The multicenter group in Australia, that whole network, is really well equipped for that because they use a PSMA cutoff of three to identify whether there's abnormal uptake, and they've used that very consistently in most of their trials.

I think in the U.S. we maybe could be able to do that, but we may have a wider variety of scanners and reconstruction techniques at varying ages, and the more recent scanners... We keep getting higher and higher SUVs for the same biology because our scanners are getting better and better, so I think... There's going to be a lot of work for us to do to be able to standardize that across the country, and that will be a potential challenge, but I think carefully designed trials could help us narrow that variability.

Phillip Koo: Yeah, I agree. Those are great points. The last topic I wanted to briefly talk about is with patient selection, the topic of FDG PET CT comes up, in large part due to the TheraP trial from Australia. How do you use FDG, and how would you recommend the community think of FDG as another tool to select the right patients to undergo PSMA therapy?

Delphine Chen: Yeah, for sure. So we use FDG more as a prognostic biomarker, and we use PSMA PET as a predictive biomarker, so when we are looking to evaluate our patients, PSMA PET is the first line. They have to have PSMA expression. If they don't, then it's not worth pursuing the therapy at all, and in those cases if the PSMA... If there's clearly low or no PSMA expression we sometimes will not even bother getting the FDG, depending on the clinical circumstance. Sometimes we may still, if there's a clinical reason for it.

But otherwise, once they have PSMA expressing disease, we still do get the FDG PET to make sure there isn't a lot of discordant disease, and we do also look at the intensity of FDG uptake as a potential biomarker. Are they more likely to get through all six cycles or not, and if they're not, we just try to have a conversation to set expectations with both the oncologists and with the patients, that they know that, okay, if we have to prepare for something sooner rather than later, that may trigger earlier restaging scans for example, or an earlier trigger to stop therapy, so we use it in that context.

And we have had situations where if the PSMA expression is borderline... So with the VISION trial you had to have uptake that was above liver in all the lesions, but if we see patients with some of the lesions, or a good proportion of them, with uptake that's similar to or just maybe minimally above the liver, the FDG PET can be helpful then too in terms of if there's very high FDG uptake, would that tilt us towards choosing another therapy versus proceeding with Lutetium and seeing what benefit we can get out of it before we proceed with another therapy, so we do use it in that context also.

Phillip Koo: Great. I love that thoughtful approach. PSMA PET is more predictive. The FDG would be more prognostic. So I guess it's safe... Is it okay to put words in your mouth to say that it's not necessarily a requirement to get an FDG PET though in your patients?

Delphine Chen: Yeah, and that's... From the VISION trial, that didn't include FDG PET. We know that if we followed those eligibility criteria the progression-free survival benefit was clear, and so I agree that there's data to suggest that it may not be absolutely required. However, we have found in our clinical practice that it is very helpful for helping to refine or... There's more nuance always in these molecular imaging tests, and so it helps us have more nuanced information to be more informed about how to work with the oncologist in managing the patients.

Phillip Koo: Well, great. Those are really nice insights. Appreciate you taking the time to join us today.

Delphine Chen: Yeah, thanks. Thanks so much. This is again, a great topic of conversation, and I'm looking forward to see how it develops.