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Alicia Morgans: Hi, I'm so excited to be here today with Professor Michael Hofman, who is joining me from the Peter MacCallum Cancer Centre in Melbourne and also recently joined me at the APCCC 2024 in Lugano, Switzerland. Thank you so much for being here with me today, Michael.

Michael Hofman: Thanks, Alicia. It was such a great meeting in Lugano.

Alicia Morgans: It was a wonderful meeting, and you really helped to illuminate some questions that we had. Certainly, no pun intended, but we learned from you about how different ligands may be similar or different when it comes to imaging and theranostics. Can you share a little bit about that, please?

Michael Hofman: Sure. So I gave a talk at APCCC Lugano on alternative PSMA ligands for both diagnostic PET-CT imaging and treatment. This is a really interesting topic because increasingly we are getting a little spoiled for choice, and clinicians may not know the difference between these ligands and whether they're going to achieve the same outcomes for their patients. I actually started with a bit of an analogy about coffee because, when I travel to conferences, one of the things I miss most is the coffee that we have in Melbourne. I'm very used to the flavor, but you travel around the world and you get different coffee flavors. So it's the same product, but there are really subtle differences, and quite often I miss my home brew.

So, when it comes to PSMA ligands, are they all the same? We’re going to start with imaging. There are four ligands in widespread use around the world at the moment. Gallium PSMA-11, which was the first. It's almost 10 years since we did our first Gallium PSMA-11 at Peter Mac, and it's been in use for 12 years or so. DCFPyL, which has been around probably for almost a decade now. These are both FDA approved. A third ligand, rh-PSMA-7, is the most recent FDA approved. Then we have a ligand on the right called PSMA-1007. If we look at the bio-distribution on these images, they look relatively similar, but there are differences.

The three FDA-approved ligands have similar liver uptake. This is really important because, as imaging doctors, we use the liver as a reference. Particularly if we're going to select a patient for radioligand therapy, we say, is the uptake above the liver? PSMA-1007 on the right has much higher liver uptake. There are also some differences in bladder uptake, which can be good if you're trying to image the prostate gland, with two of these tracers having lower bladder uptake.

The two on the left have been around for a very long time, and I think I made the point that they're really equivalent. Gallium PSMA-11 and DCFPyL have extensive experience. If you look at the normal organ bio-distribution, it's really similar. We actually did a study where we took patients in our center who had both of these scans at different time points but the same patient, and we compared the uptake in normal organs. It was virtually identical. In my experience, these tracers are really interchangeable. While we try to use the same tracer if a patient is coming for staging or re-staging, even if you mix it up a little bit, it doesn't matter too much. They are so similar. I think we can say they're equivalent.

In Australia, we have an interesting phenomenon where our PSMA PET is reimbursed, but the reimbursement is agnostic. The item number just says PSMA PET. The clinician, the nuclear medicine doctor, can choose whatever PSMA ligand they want. This is obviously very different than in the US, where you're regulated by the FDA. This means we kind of democratize choice. In Australia, all of these agents except rh-PSMA-7, which is not yet available, are in widespread use. Some people say one is better than the other. We looked at phantom studies and made the point that you really can't differentiate. There are quite subtle differences between these, but if you look in the detail, maybe the gallium does have lower imaging quality, but you really can't pick this in real life. What about tumor uptake? How do they differ between the tracers? We actually don't have any comparative studies. All these studies compare the PSMA ligand to a CT and bone scan, and clearly, they're all superior to CT and bone scan, but it doesn't tell us how they compare to each other.

I think this era needs to end. If you have your next-generation PSMA ligand, you really should be comparing it to one of the FDA-approved ligands rather than going back and saying, my new agent is better than a CT bone scan. I made a special point about PSMA-1007. This is in widespread use, particularly in Europe, and also in a few parts of Australia. One of my colleagues, Professor Patterson from Brisbane, actually did a comparative prospective study comparing Gallium PSMA-11 to PSMA-1007. He wanted to show that they were equivocal, but he found what was known: there's this benign bone uptake with the fluorine PSMA-1007, and it can be quite problematic. This is not a sternal metastasis; it's just benign uptake, perhaps from a prior injury. We see this quite frequently in the ribs but in many other sites as well. He found that this occurred in almost 50% of patients, and the intensity of uptake was quite high, 6.2.

And whilst you can decrease this with reader experience, it's really quite problematic. And in his center, I understand he's actually abandoned the use of PSMA-1007 after doing this study, the exact opposite of what he wanted to show. So I think we need some caution with this particular tracer, which is not FDA approved. And then the second half of my talk is on the therapy. Are the radioligands for therapy interchangeable? And today we really only have two to choose from and they are PSMA-617 or PSMA I&T. And actually the PSMA binding motif on both is virtually identical and the same as the gallium PSMA-11. What differs is the chelator, which is the molecule that bonds the binding motif to the radioactive substance. And actually these have been in widespread use for some time. Actually, the use of PSMA I&T slightly predated 617 in Germany. 617 was obviously commercialized first and therefore we have a larger evidence base, many more publications, and many more prospective trials using PSMA-617, including obviously the Vision and the Therapy trial.

For PSMA I&T, there is no published prospective data really to date. We have some trials underway such as SPLASH and ECLIPSE, but no published results to date. But we do have extensive off-trial use, which is not represented in this publication chart, but really in many parts of the world, this has been used for over a decade. And I don't think we can just throw out that clinical experience. And I highlighted some meta-analyses showing that really these two ligands, they seem to be equivalent and we could potentially use the word radioequivalent because we can measure after we give an administration of a radioligand the dose to both normal organs and tumors and we've published on this and then we can compare data of PSMA I&T and PSMA-617. And we need to ask the question, is radioligand therapy a drug or is it a type of radiotherapy?

In the radiotherapy model, we use dosimetry to define the dose to normal organs and we don't want to exceed that. And we can also look at doses to tumors. In the drug model, we don't need dosimetry or post-treatment imaging. We just give the drug and then we escalate the dose of the radioactivity we give and we see how much is tolerated and we can observe the acute toxicities. And there's a bit of a flux here because this is obviously not external beam radiation. You can't control how much radiation is going to particular sites, but I think on this graph I would sway more to the radiotherapy model. It's essentially a radiation delivery device. If we don't get the radiation to the tumor, we have no effect and we can measure this. And if we get very high doses to normal organs, then we can observe these toxicities.

But we need to use a little bit of both, which has been a challenge. And when we compare 617 to I&T, they are very, very similar; perhaps there's a slightly lower dose to the kidneys with 617, but the difference is so small, it's probably not clinically significant, and the tumor doses really look very comparable. And I just want to stress again that both of these have clinical experience for over a decade, and this is quite unusual. But I also made the point that perhaps the difference between I&T and 617 is probably small compared to the difference of should you treat the individual patient in front of you. And something we've been doing in Australia is really selecting patients quite carefully for radioligand therapy and we use FDG. And in this patient on the PSMA PET, if the patient looks suitable for radioligand therapy, there's multiple bone metastases, the uptake is above liver. You can't see any sites of PSMA-negative disease on the CT, but when you do the FDG, you see a vast amount of disease that is simply not PSMA-avid and invisible on the CT.

And both the PSMA and FDG were performed one day apart in this patient. So this is someone we would suggest, what other treatments are available for this patient because we don't think radioligand therapy is going to be very effective. So I encourage people out there, please don't treat blindly, select your patients carefully. We can pick at baseline with this treatment patients that are just not likely to benefit from this treatment. And conversely, we can see patients with very high uptake that we really need to prioritize for this treatment because they're very, very likely to respond. This is a unique biomarker with imaging that we simply don't have for other treatments like chemotherapy or other drugs.

So in summary, maybe the best PSMA radiotracer is actually the one you can access. Gallium PSMA-11 and DCFPyL, they're really totally equivalent. rh-7, the newest FDA approved radioligand on the block appears equivalent, but we have less experience. PSMA-1007, we really need to be aware of that benign bone uptake. PSMA-617 and I&T, look, we don't have direct comparative evidence base and the randomized data clearly is there for 617, but we have 10 years of experience with I&T and surrogate data and they seem radioequivalent. There's other choices such as antibodies, minibodies, that I didn't talk about in this brief one, but the peptides seem to win at least for the moment. And don't forget that reader experience, patient selection, technical factors, these things all really matter and they may make a bigger difference than some of the more subtle differences between these ligands.

Alicia Morgans: Michael, that was a fantastic talk. Thank you so much for really helping to illuminate some of the differences between these tracers. So let's focus for a moment on the imaging tracers. And can you tell me when you're thinking about prostate cancer patients who are in different disease states, whether they are high-risk localized or biochemical recurrent versus the metastatic CRPC setting or perhaps the metastatic setting generally when we're thinking about treatment choice, would you use a different tracer in a different disease state perhaps based on the amount of metastatic disease you expect to see or the interference that you might have from things like the bladder?

Michael Hofman: Yeah, thanks, Alicia. That's a great question. I think we do not. As a center, even if you have a choice of all of these, you're not going to choose a different ligand for this indication and a different ligand for that indication. You're probably going to choose the one that's most available to you. That varies by geography, honestly. In some places, there are gallium generators. In some places, you can get the fluorinated tracer shipped to you. These are really geographic choices depending on where you are. And in some places like ours, we can choose from different agents, and honestly, we don't say this is biochemical recurrence, we're going to choose this one because it's slightly better. It gets logistically too complicated to do that. I think the benefits are really tiny. So I think you're going to be driven by your practical aspects and, as a nuclear medicine specialist, as you get into the detail, it's good to be mindful of what tracer you are using.

And certainly when these cases come to the multidisciplinary meeting for review, our tumor board meetings and they've had a PSMA PET scan outside, I do want to know which tracer was it done with because they're not all the same. So if it's come from somewhere and it is one of those fluorinated PSMA-1007 scans, I'm going to be mindful about false positive results in bone. So I really need to know that information. And sometimes it's not even on the report. You just get the report and it says procedure. We did a PSMA PET-CT. And I'm like, "Well, that's just not adequate. You've got to tell me what procedure was done."

Alicia Morgans: Yeah, absolutely. And so interesting to see that information about the 1007, which is unfortunate. I feel like that's a catchy little name there, 1007. But I mean clearly, if 50% of these patients are going to have bone lesions that are showing up that are really false positive, that's going to be a challenge not only in centers where you have expert readers like you, but when we try to deploy this more broadly to places that do fewer PSMA scans perhaps, it could be a real problem. And I appreciate, what are your thoughts there? Do you think 1007 is going to be something that we're going to see disseminated more broadly, or should we as a prostate cancer community probably try to focus in a different direction?

Michael Hofman: Look, it's a tricky question because it depends where, again, geographically, where you are. And there are some IP issues and access issues with these peptides, and we didn't go into the detail of that, but if you can access 1007 and you can't access the other ligands, then it's still actually very, very good. It's vastly superior, I would say, to a CT and bone scan. And when we talk about false positive results, honestly, you can't trump a bone scan for false positive results. As a nuclear medicine specialist, I spend a lot of my time reporting bone scans as well, and they're completely nonspecific. Fractures, benign uptake will light up as brightly as a prostate cancer metastasis on a bone scan, so you have no specificity. So a PSMA-1007 scan is still way better than probably CT bone scan, maybe even MR in the right setting. So it's still very good.

And with reader experience, I think there are publications showing that once you're aware of this false positivity with that tracer, you can under-call, look at the CT more closely. Is there a correlative abnormality? Or order a second test like an MR if you're concerned that it could be a false positive. So there are strategies to get around that. So I think you do need to work closely with your imaging doctors to work this out, but if you are spoiled for choice and they're the same price and same accessibility, then I would not choose PSMA-1007.

Alicia Morgans: I think it gets back to some of your comments on appreciating the home brew. You appreciate what you learn with what you really train on, what you use on a regular basis. I think that's such a wise comment and really a wonderful analogy there because I do think it's often true when we're thinking about therapeutics that we reflexively return to the treatments that we know we can manage, that we trust the therapeutic index. And it's interesting that that is also the same and of course, it's the same for physicians who are dealing in nuclear medicine.

So final question here, as we kind of think about the therapeutic aspect, it's really interesting and we don't yet have data, of course, from the I&T products, but it's really interesting to think about that availability and how it has been used without the FDA's indication because it's not necessarily being used in the United States, it's being used around the world. Where do you see that going? And obviously, this is a very forward-thinking question and not a question that I expect you to know a correct answer on, but it's really interesting that we may be getting data on some of those trials relatively soon, and there may be access reasons why this is important for around the world to have this information on I&T, even though we also have options with 617.

Michael Hofman: Yeah, it's a great question, and it's an evolving area, and there are two elements to this. One is regulatory approvals and FDA approval, which is particularly relevant to the US market but has obviously influenced globally. Another is legacy. This is unusual because usually when you've got a second product that's not approved, it's a newer agent. You're wondering if it is the same or different. Here, the use of PSMA I&T predated 617. The very first series that I saw was a 37-patient series from Richard Baum using PSMA I&T. That struck my interest in this area. Then we did the first prospective trial of PSMA-617 in our center at Peter Mac. So we have an unusual situation where we have extensive clinical experience and we can't just throw that out. If we didn't have that, I think I would just go strict and say, show me the data, go and do trials.

But in many countries like India, South Africa, and many parts of Europe, PSMA I&T has been used for so long, and so many patients have been treated with positive results, and also in Australia. We get a sense from all the data that they're really extremely similar. So I think your choice again depends on where you live. If you live in the US, this is not an option. You use the approved product. If you use an unapproved product, that's illegal, and you can't access it. And PSMA-617 is now approved, perhaps reimbursed. You're going to choose that agent 100% for sure. But if you can't access 617 and you live in India and you can access I&T, you're not going to fly to the US to pay for 617, you're going to access what you can have locally. And I think I'd feel pretty comfortable that you're probably going to have similar outcomes.

So the challenge here will be as we look at some of the newer trials like SPLASH. It's not just I&T, but they've chosen a different dosing schedule to 617. So it uses a slightly lower dose and eight weeks rather than six weeks. And we can be a little bit critical of some of these choices. So that's not something that you would do in clinical practice if you're applying I&T. So there's lots of complexities here. It's a rapidly evolving area. Again, it's good to have choice for our patients. I think the way this evolved is different from a conventional drug manufacturing process with a phase one, two, three trial. If we go back 10, 15 years, PSMA therapy evolved in nuclear medicine departments as an academic exercise, and we've got that legacy, and we can't sort of untangle all of that. So it's a little bit complicated.

Alicia Morgans: Michael, I so appreciate you getting into the weeds with this and with us today. It was so informative, not just the same PSMA Lutetium talk that we have heard coming down and not just a data-focused talk, really thinking about some of the broader issues. I so appreciate it. Thank you so much for your time and your expertise.

Michael Hofman: No, thanks, Alicia. And I think that's the great thing about the APCCC meeting, is that it's focused on these tricky areas. On purpose, I didn't have an evidence-based talk today, and I really like evidence-based medicine, but there are only so many questions a phase three trial can answer. We can't do a phase three trial to answer every single question in medicine. So we need to get into these nuances every now and again.

Alicia Morgans: Well, it was wonderful. And thank you again.

Michael Hofman: Thank you.