The Mechanism of PSMA PET for Prostate Cancer - Stefano Fanti and Ken Herrmann
November 16, 2021
Independent Medical Education Initiative Supported by Novartis/Adacap and Point Biopharma
Stefano Fanti, Professor, Department of Experimental, Diagnostic and Specialty Medicine - DIMES at the University of Bologna. He is Director of Nuclear Medicine Division of the PET Unit at the Policlinico S. Orsola and Director of Speciality School of Nuclear Medicine at the University of Bologna.
Ken Herrmann, MD, MBA, Professor and Chair of the Department of Nuclear Medicine, Universitatsklinikum Essen, Essen, Germany
Ken Herrmann: Hello everybody. It's my great pleasure to welcome you to the PSMA PET Academy. Together with my great friend, Stefano Fanti, I will introduce you to PSMA-based PET imaging. And I welcome you now officially in the red corner, Professor Stefano Fanti from Bologna.
Stefano Fanti: Thank you very much, Ken. It's a great pleasure and honor to be here and try to give you some clues and clarify whatever we can regarding the PSMA-based PET imaging. And you can see on the left blue corner, we have Ken Herrmann from Germany. Well, the leading country to every extent and pioneering the PSMA. We'll go through that in our presentation.
Ken Herrmann: Here we go with the learning objectives. First of all, we want to introduce you to PET, get familiar with PET. Then we want to focus on making you understand the range of various PET tracers. We want to talk to you about the concept of PSMA theranostics, and obviously, we want to make sure that you feel the urge to hear more about PSMA PET.
Stefano Fanti: Yeah. And for that, this is the outline of our talk. We will start with some principle of PET imaging and then we will talk about PET tracers. As you can see there are many from FDG, choline, and so on. And then we'll get in detail into the PSMA tracer, and finally we will give you some little clues about theranostic, this magic word that is so much used nowaday.
Ken Herrmann: Now Stefano, I'm really curious to hear more about PET imaging.
Stefano Fanti: Yeah. Well first of all, as I used to say to my student, the first thing you have to know is the fundamental difference between functional and anatomical imaging. Usually what we call the traditional radiological approach. So namely ultrasound, CT, and of course standard x-ray, but also MRI is providing you anatomical information. So morphological imaging which is fundamental but not always enough. So in some cases you need functional information. And that's typically what nuclear medicine can provide to you and in particular with PET. That's the very simple concept.
And with that, of course, we have the PET tracer. So any tracer has some very peculiar characteristic that are functional characteristic and will provide you information in a different domain. So for example, we have metabolic tracer that goes within a metabolic pathway. And typically is FDG for glucose pathway or sodium fluoride, choline for the membrane turnover, and fluciclovine that's a synthetic amino acid. And on the other side, very different, there are the receptor tracer, just like somatostatin receptor in neuroendocrine tumor and most of all PSMA in prostate cancer.
Ken Herrmann: So that piece may really make a difference. And I think this is a great example from Bologna showing very simple, by just looking at the maximum intensity projections of the same patient within a few days that indeed PSMA is super more sensitive than choline. And this is actually so obvious that it doesn't really need to be medical education nor spending five years in medicine to see that there are many more dots on the right side compared to the left side.
And yes, PSMA PET seems to be a game changer. Now one example is never really enough to make a case. And so I want to cite this very nice perspective trial from UCLA in 50 patients comparing perspectively Gallium-PSMA-11 is FACBC. And here it was clearly shown that PSMA PET has an edge over established fluciclovine. So Stefano, you are older than me. So tell me more about the history and the story of PSMA.
Stefano Fanti: With pleasure. But please don't remind me how old I am. But in any case I was there, well we both were there, when the PSMA story began. Indeed the PSMA as a receptor was already studied in the late '90s, but the key difference came from Heidelberg. That it really used this small molecule labeled with gallium that enabled us to have nice images. And we were all impressed by this first publication from Ali Afshar-Oromieh and the group of Uwe Haberkorn demonstrating the superiority of Gallium-PSMA over in that case F-choline.
And the story went on. So we can see that after nine years, we have an impressive amount of literature, more than 2,000 articles. Well this year already 500 articles. And to every extent we have become part of the most authoritative guidelines as EAU, NCCN, ASCO and others. So the mission I can say is accomplished. PSMA it's around and we will not come back for sure.
Ken Herrmann: So Stefano, there are many different PSMA tracers. And I think our colleagues from oncology and urology, they do not really have to know all them in detail. But we both agreed on highlighting those two. And the main reason is that on one side the Gallium-PSMA-11 not being only the first PSMA PET tracer vitally available, but also the first who was FDA approved. And the second one we want to highlight quickly the PyL, because all these tracer now has been recently FDA approved.
Interesting to mention, the U.S. started much after Europe, but in contrast to Europe there already two compounds approved. Also something very important when we talk about the differences between gallium and fluoride. And this is actually the example of which we want to show you that first of all, they all have a very, very similar biodistribution. Which means all of them in common, you see a lot of uptake in the [inaudible 00:06:12] agents, and this is independent of which tracer.
You also see quite some uptake in the liver and the spleen, you also see the kidneys. But it now comes a difference a little bit some of the tracers, for example, the ones on the left side, the four on the left side are mainly excluded where the kidneys and the urinary tract, so we see also quite a lot of physiologic uptake in the bladder. Whereas the two on the right, they are mainly excluded via the GI tract and there you see much less uptake.
For example, in the bladder which makes it easier as we will see later it will detect a focal uptake in the area of the prostate, the prostate part or around the bladder. Also important is that the gallium until now is mainly a product from the generator, has a half-life of 68 minutes. In contrast flu-18 cyclotron product and potentially with a longer half-life and the possibility to synthesize larger amounts of flu-18, has some slight logistical advantages. But this being said, Stefano, what do you think who's the winner?
Stefano Fanti: Well, let first of all the game, the match begin with the premises that you mentioned. That for us as nuclear medicine physician it's quite trivial the concept of a basket tracer. That say ligand which is specific for the same target, but at the same time different compounds just like PyL and PSMA-11 here. And this slightly different characteristic that may or may not imply clinical difference. Because in some cases biodistribution makes a difference and in other does not.
So for example this preliminary study, comparing PyL and PSMA-11 essentially ends in a tie. So the performance, the results are almost the same. But we have other match, other comparison, that's fluorinated 1007 and PyL. In this specific report, it was emphasized that some lower background in the liver may favor PyL. But we have to be honest, the metastasis is in the liver are not really the key reason why you're using PSMA. Because for example, MRI and CT works perfectly well on the liver. But other competitors are there. And probably do you agree with me, this is the hottest fight in PSMA history? Especially in Europe, the competition it's about Gallium-PSMA-11 and fluorinated-PSMA-1007.
Ken Herrmann: I'm happy that you mentioned this, Stefano, because this is also the question we hear quite often from our clinical friends, right? From urology and oncology. So what is your opinion here?
Stefano Fanti: Well apart from the logistical differences, the fact that you mentioned it, you need a cyclotron or you need a generator and different radiopharmaceutical characteristic. By the diagnostic performance characteristic, I like this paper again run by some of your German colleagues that reported a much higher number of lesion of benign origin with fluorinated-PSMA-1007. That say a potential cause of phase positive findings, which is absolutely more relevant and therefore more worrying for the fluorinated-PSMA-1007. So despite, we cannot really say there is a ultimate winner because the match has not been run, let's say, in a regular setting with the referees and so on. But those data are quite significant in that. We have [crosstalk 00:09:57].
Ken Herrmann: Is there more data, Stefano?
Stefano Fanti: Yes, there are some other studies but honestly, the data regarding staging so slightly different indication but also in patient with already confirmed diagnosis. There may be a little advantage for the lower urinal excretion of PSMA-1007. But the same time, in my view, this is not overcoming the advantage regarding the potential of phase positive funding. And by the way, I guess, that you perfectly know that regarding the so-called UBU, correct?
Ken Herrmann: Yeah. The phenomenon of UBU we actually dedicating one slide to this because it has been really addressed quite frequently in the last weeks and months. And this is a very nice paper from Switzerland. It's a retrospective analysis where they really looked at more than 300 patients, all undergoing PSMA-1007 PET. And indeed here in more than 50% of the patients, a so-called unspecific bone uptake was found.
When we look on the right side, we can see that actually this is most frequently seen in ribs, less frequently but still quite frequent in the pelvis, and in very low numbers in the extremities, sternum, skull, and a little bit more in the spine. Also very interesting reported from the Swiss group is that these unspecific bone uptake is especially prone on so-called very sensitive, modern digital PET scanners as can be seen here. And also more frequent at an uptake time, 60 minutes after injection compared to a later time PET imaging of 90 minutes.
And to close up our fight session here, this is another paper comparing PSMA-1007 with other tracers. And this group quite nicely actually mentions it indeed. If there are certain findings which are close to the urinary bladder or close to the urinary tract, there is a certain benefit of PMSA-1007 as it's mainly excluded via the GI tract. On the other side we do have these unspecific bone uptake, which is more frequently found in this kind of PET tracer. And in this group, actually, they do not like to weigh, but they clearly mention that the unspecific bone uptake might be a bigger challenge than looking at lesions nearby the ordinary tract. So what is the next big thing, Stefano?
Stefano Fanti: Well, now we promised to spend a couple of minutes about theranostics. Theranostic is this magic word that's become so frequently used. And the concept is very simple and it's in our end, so [inaudible 00:12:38]. And that's to say you can treat what you see, the citation is from Wikipedia. So it's really a mix of therapeutics and diagnostic proposed as a process in which you target a target. I mean, you try to be as specific and sensitive as possible with your target, and then you use those information to treat. So the same target is used for therapy.
And so you can really drive very innovative therapies that fully benefit the range of isotopes that we have available. And again if we move to the next cartoon, that's typically... I mean it's not exclusively of nuclear medicine because our specialty can do that. But for us is fantastic because whenever you have a target that can be addressed and properly used with link and a ligand, then you can add your isotope. And if the isotope as diagnostic function. So if it's a positron or a gamma emitter, you can see the cancer. But if you are using alpha or beta minus emitters, then you can treat.
And again I use for my student this very trigger example in the next figure. If you use gallium or a fluoride, then you can see. So you have a light because you have at the very end a photon coming out and providing you the nice images that we have seen before. But if you replace that with a different isotope, like lutetium or actinium or yttrium then you can definitely kill the cancer. So that's the basic simple concept of theranostic. That it's so relevant nowadays with the new product coming into the market.
Ken Herrmann: Stefano, what a great comparison, really easy to understand. And we actually reached already the finish line of our first introductory part. But our conclusions. First of all, we have made you familiar with PET, so I think this mission is achieved. You do now understand the range of different PET tracers, especially different PSMA tracers. We introduced you to the concept of PSMA theranostics. And Stefano, I think we both deeply hope that you now feel the urge to hear more. So please stay tuned and look at the following parts of the PSMA PET Academy.
Stefano Fanti: Thank you. Stay tuned.