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Oliver Sartor: Hi, I'm Dr. Oliver Sartor, and really a pleasure today to be able to welcome Ken Herrmann on UroToday, one of the leading lights in the world and chairman of the German Nuclear Medicine Department at Essen, a professor there. Welcome, Ken.

Ken Herrmann: Thank you very much, Oliver. It's a great honor to be with one of the big godfathers of radionuclide therapy in a conversation, Oliver. During ESMO 2024, I think it was a great opportunity for me to talk about the state-of-the-art of PSMA ligand therapy, especially given the fact that just seven years ago there was, I think, one talk about nuclear medicine at ESMO, and now we had the great pleasure to be really a significant part of this beautiful conference.

To kick it off, I want to show you a question which was asked to the expert panel at APCCC in Lugano earlier this year, and the question was, if patients who are chemotherapy-fit and also had a PSMA-positive lesion in the mCRPC situation and who had, as a prior treatment, one line of ARPI, no chemotherapy, what would be the preferred next treatment?

Very important to mention, nuclear medicine physicians were not allowed to vote, so this is really the expert panel. And you can see, indeed, here that 70% chose option three, which was as next line of treatment to go for chemotherapy. The same question was repeated in patients who were not asymptomatic, but in this case symptomatic. And again, same situation. Patients with mCRPC, only one line of ARPI, no previous chemotherapy. Here, you can see that now 82% of the panelists opted for docetaxel. Very important to mention, when 75% of the voters agreed on something that this was a consensus. And this data, by the way, is now with Silke Gillessen and Christian Fankhauser as first and last authors, also online available in European Urology.

Now, the same question was asked now in a different setting. Again, patients fit for chemotherapy, mCRPC, same setup as the patients before, but in addition to one line of ARPI, they also have already one line of taxane-based chemotherapy. And you can see, again, the corresponding options, and very obvious here, 96% voted for lutetium-PSMA. I think this is super exciting, Oliver, because this is exactly the line of treatment which was introduced by the VISION study, the pivotal study leading to the approval of lutetium-PSMA-617, so-called Pluvicto, by both FDA and EMA.

Now, a very important study, obviously, is the PSMAfore study, trying to bring lutetium-PSMA one line earlier. In this case, patients with mCRPC who had one line of ARPI were randomized into either ARPI switch or into lutetium-PSMA-617. The primary endpoint of the study was rPFS, and we can see very nicely here that the median rPFS was 5.6 months for the ARPI switch arm and 12 months for the lutetium-PSMA arm. Very timely, during ESMO, this paper was actually published in Lancet with Michael Morris as first author. Also interesting to mention, even though overall survival was just a secondary endpoint, here we can see it in the tertiary analysis, in the third interim analysis, the hazard ratio was below 1, 0.98. We see the curves do cross, and the median overall survival in both arms was around 23.7 or 23.9 months, respectively.

Important to mention, there was a significant crossover of patients. You can see here that 78% of eligible patients from the ARPI switch arm actually crossed over to lutetium-PSMA-617. The overall story of PSMA radioligand therapy is to get into earlier lines, just very quickly highlighting here the two prospective phase III studies. On one side, the PSMAaddition study where we performed lutetium-PSMA therapy in hormone-sensitive prostate cancer. Patients get randomized 1:1 to standard of care, which, of course, is an ARPI as the standard of care, plus up to six cycles of lutetium-PSMA every six weeks. Primary endpoint is rPFS, and again, also here I think the absolutely very appropriate option of crossover.

On top, one of my most preferred studies significantly initiated by Oliver Sartor, the delayed castration study. I think it's a very important study. In this case, patients who are M0 on conventional imaging with biochemical recurrence and who have up to five lesions on PSMA PET, they will undergo SBRT to all metastatic lesions and they're randomized on top to this 2:1 into getting up to four cycles of lutetium-PSMA. Very, very interesting. The primary endpoint of the study is metastasis-free survival based on conventional imaging, but the secondary endpoint, which I care so much about, is the time to start of hormonal treatment. I think this is a very, very interesting, very important study.

Now, even earlier in the line of therapy is performing lutetium-PSMA prior to prostatectomy. On the top, the front-runner of this study is the Lu-Tectomy study from Australia with Renu Eapen as the first author published in European Urology where they showed that, indeed, administering lutetium-PSMA-617 intravenously—first one cycle, then another 10 patients, two cycles—is safe. The primary endpoint in this case was actually absorbed radiation dose. Even more important also to understand how safe it is to treat these patients with surgery. And the results were very compelling. Every patient was able to undergo surgery. We have also seen very nice movies from surgery from Declan Murphy, seeing that, indeed, this was absolutely feasible.

Based on these two studies, we have also two ongoing in Essen. On the left side is the NEPI study. In this case, a combination of lutetium-PSMA with ipilimumab, either two cycles of first 3.7 then and later 7.4 gigabecquerel plus ipilimumab. And here primary endpoints in addition not only to the feasibility of performing the surgery, the potential delay of the surgery, but also, of course, efficacy and pathological response.

On the right side a very interesting one, this is the so-called LUPUS trial where we perform lutetium-PSMA, again, prior to surgery, but in this case intra-arterially. The first 10 patients received 7.4 gigabecquerel. Another 10 patients double the dose, which is currently approved in the VISION setting and it's administered intra-arterially. The idea of this intra-arterial application is that we get a higher uptake in the prostate, a higher radiation dose, and hopefully here we will also see a couple of complete pathological responses.

Another very interesting study also published at the same time at ESMO in Lancet Oncology, presented at ESMO by Arun Azad as an UpFrontPSMA study. Very interesting because it's the first prospective study using lutetium-PSMA in mHSPC. Here the idea was to randomize patients to either chemotherapy alone versus chemotherapy plus two cycles of lutetium-PSMA. The primary endpoint was a detectable PSA at 48 weeks, which was highly statistically significant.

Another very interesting combination study on the right side is the ENZA-p trial, with Louise Emmett as the first author, recently published at Lancet Oncology. We are very nicely showing that patients in mCRPC who receive enzalutamide, they had a significantly better likelihood to have PSA progression-free survival if they received, in addition to enzalutamide, lutetium-PSMA. This is also the case on the bottom, which you can see the clinical progression-free survival very much in favor of the combination of enzalutamide plus lutetium-PSMA. Here we are, of course, very anxiously waiting for the overall survival results, and this is something which is going to be presented very, very soon.

This actually brings me to the last slide. We see that a lot of questions are arising around the treatment of prostate cancer related to imaging, not only imaging but also other blood parameters like, for example, the Decipher score or ctDNA. Overall, we think that this is a very timely topic to really focus on diagnostics, and that's why I'm very happy to actually show you this slide with four very, very well-known giants of diagnostics in prostate cancer. You can see here Tom Hope, Louise Emmett, Stefano Fanti, and Michael Hofman who will all participate in APC Diagnostics. Oliver Sartor is going to participate in APC Diagnostics, and it's my great pleasure to invite you all to come hopefully to Lugano at the end of February next year.

Oliver Sartor: Gosh, thank you, Ken. That is such a beautiful overview of the recent past and future in terms of trials. I'm not even sure where to go next, but I might dive in a little bit to ENZA-p. The reason I might dive into ENZA-p is that it was a very strong effect with an interaction between the enzalutamide plus lutetium as compared to the lutetium alone. And we contrast that, if you will, with the PSMAfore trial, where it was monotherapy kind of forced upon the sponsor because the regulatory agencies wanted to view the use of lutetium as a monotherapy, not as a combination, unlike VISION where it was standard of care plus or minus.

So I wonder if just for a brief moment you might compare and contrast the PSMAfore and the ENZA-p studies. From your perspective, how do you think about it and would it be preference in the way you think about it? So I'm just interested in your thoughts, and you have a wonderful perspective on the field. So your thoughts on these two studies as they line up.

Ken Herrmann: Oliver, you are, of course, immediately identifying, let's say, the only beauty mistake of ENZA-p, that there's a third arm missing. We have Enza, we have Enza plus lutetium-PSMA, and we don't have lutetium-PSMA alone to actually show exactly what you just mentioned. We both anticipate that lutetium alone is probably significantly inferior to the combination of Enza plus lutetium-PSMA. Can we really extrapolate this from what we have seen in PSMAfore where lutetium was given alone? Probably not for a couple of reasons.

First of all, ENZA-p, I think more than 40% of the patients had chemotherapy in a hormone-sensitive setting, if I remember correctly. For PSMAfore, I think none of the patients had chemotherapy before. So it is really different overall, and I think this also underlines very well. One of the topics which was presented at ESMO 2024 was the PEACE III dataset from Silke Gillessen, which again is Enza versus Enza plus radium-223. And there also we saw a very compelling survival benefit and also especially an rPFS benefit, which again comes to the point that I personally think that we are still underutilizing or underappreciating the additive effect of both ARPI plus the lutetium-PSMA.

And coming around totally, as you mentioned before, in the VISION study, I think around 50% of the patients had as a standard of care an ARPI, which means 50% of the patients also had ARPI plus the lutetium-PSMA. And we are currently waiting anxiously for the subanalysis, but we both, I think, have a suspicion that the patients who had an ARPI plus the lutetium-PSMA are the ones who benefit the most from the lutetium-PSMA.

Oliver Sartor: Thank you. Love your perspective. Another issue that is generating some controversy, I think, behind the scenes is the dosing that we have adopted. And I wonder whether or not you think that the dosing of the PSMA lutetiums are optimal, suboptimal, or just perfect?

Ken Herrmann: This is an easy question, if I can really do this in an ABC manner. It's definitely not optimal. It is far from perfect, and I also think it's pretty much not optimal. I mean, again, where does a number come from, right? Originally we all know that this was initially already used for neuroendocrine tumors. It's a very even number, 200 millicuries, right? It's calculated to 7.4 gigabecquerel.

I think we have now all understood that we are probably heavily undertreating the majority of patients. We are not taking advantage of the full therapeutic index. Also, I think one phenomenon we are going to present at E&M is where we really look at the VISION subcohort and we look at the tumor dose over the six cycles administered. And what we see is that the dose we achieve per injected activity actually decreases from one cycle to the next cycle. And this, again, comes to the point how should we reconsider dosing?

It's probably we should give a higher activity up front, and then be more willing to adapt and reduce over time. Does this mean we are going to give double the dose in the first two cycles and maybe only half the dose as a kind of maintenance? Or should we do, for example, Australians reduce from one cycle to the second cycle by half a gigabecquerel? This is something we need to look at. But you're absolutely right. Currently, we are a lucky shot, but we are definitely not taking full advantage of the therapeutic index which is available.

Oliver Sartor: Appreciate your perspective. PSMA-DC is an interesting study that I think has some controversy. I'd like to go to the heart of that controversy and hear your perspective. So we're going to be looking at the oligometastatic disease, and every spot that is seen is going to be radiated with external beam. Now, that leaves only the spots that are unseen to be treated with lutetium. Do you believe that lutetium might be able to treat not only what you can see, but what you cannot see? And if so, I'd love to hear your thoughts.

Ken Herrmann: It's an excellent question. First of all, yes, we have one very powerful therapy and we try to explore it from different angles. The first angle is late line where we really treat what we see. And I think it's a very compelling, very good argument, and I really like that. On the other side, we go now to very early lines where we try to actually treat micrometastases, micrometastases which, by definition, we cannot see. That's why it's micrometastases.

The interesting thing is even though the concept is completely different because we really want to treat what we don't see yet, I really believe it's possible. And it's not even taking away from nowhere. We have actually a lot of experience in this already when you go back to the thyroid cancer treatment. There, we actually use radioiodine after the removal of the macroscopic tumor, at least most cases of the microscopic tumor as well, and we use it as an adjuvant.

Now, is this going to work? We don't know, but it's of course a very compelling scenario. I think that's why we both know very well that patients, a lot of male patients, do not like castration or do not like hormonal treatment. They're willing to find ways to delay this as much as possible. And for this, the concept of micrometastatic treatment is, of course, something very compelling. Does it work? Something that we have to show. Is lutetium the right thing to do or maybe at a later time point actinium because we are even more focused? Something we need to find out.

But also something I think is really important also is every therapy comes at a certain cost. And by this I not only mean the financial burden, but I also mean the toxicity. And we now need to test a little bit what is the right amount of toxicity we are willing to accept for a certain incremented delay of, for example, castration. And that's why I think it's the right thing that we start with lutetium. But let's say even if maybe lutetium doesn't work, doesn't mean automatically for me that we have to completely cancel this approach. But then we might have to rethink, reconsider if maybe alpha would be a better way to do this.

Oliver Sartor: Excellent. Ken, we're going to be having to wrap up here in just a moment, but I wonder if you might have any final thoughts or something you'd like to share with the audience that we have not covered today. I think you and I could probably talk for about three or four hours and still have plenty of ammunition to go after that, but any final words or thoughts for our audience today?

Ken Herrmann: Yeah, I would like to finish saying thank you because, like I said before, I'm in a tremendous position. We came to this game six, seven years ago. We did not know much. Not saying that we know so much more now, but the way urologists and medical oncologists embraced us, allowed us to sit at the table and work with you, something I'm truly grateful for and I know that this is nothing we can accept as something given. We now will see something similar, I think, in the other two entities, and I'm not sure that this will be as pleasant, as easy, and as enjoyable as it was with medical oncology and urology. Thank you, Oliver.

Oliver Sartor: Well, thank you. I think multidisciplinary care is key to progress, and I think you represent part of the progress that we need to embrace. Really a pleasure to have you here today, Ken, on UroToday. Really enjoy the conversation.