Bernd Krause: Hello, welcome to the PSMA Academy. Today's case is on PSMA-PET/CT before and after PSMA radioligand therapy, with a mismatch example for liver metastases. My name is Bernd Krause. I'm a nuclear medicine physician, and I'm from Germany, from Rostock Medical Center in the Department of Nuclear Medicine. And it's a pleasure for me to have this session together with Professor Sartor. So, I would like to hand over to Oliver. Oliver, please.

Oliver Sartor: Great. Thank you very much Bernd. I'm Dr. Oliver Sartor from Tulane University in New Orleans. I am a medical oncologist, but have had a long interest in the radio pharmaceuticals and Bernd and I were the co-PIs on the VISION trial recently for PSMA-617 Lutetium. So, pleasure to be here today and look forward to the discussion.

Bernd Krause: Thank you Oliver. So, then I would like to start with the presentation of a case. So, the case is on PSMA-PET/CT before and after radioligand therapy with a mismatch example on liver metastases. So, this is a case on a patient with locally advanced prostate cancer with nodal, osseous and liver metastases. The Gleason score was 4 + 5= 9, initial diagnosis in 2018, with a BRCA-2 mutation. This is the patient history. The patient had one neoadjuvant antiandrogen treatment in late 2018. He underwent radical prostatectomy and lymphadenectomy, also in late 2018, R0 rejection. He suffered from a biochemical recurrence as early as June, 2019, followed by radiation treatment and antiandrogen treatment.

And progressive disease developed, was nodal and osseous metastases. So as you see a first line docetaxel in 2020, enzalutamide, 2020 and '21. olaparib in '21, and cabazitaxel in late 2021. And concomitant medication was leuprorelin. There was a significant increase in PSA up to 137 nanograms per milliliter. And so the patient was presented in the interdisciplinary tumor board in February, 2022 for potential PSMA radioligand therapy. So this is the gallium 68 PSMA PET/CT before the PSMA radioligand therapy. So this is March, 2022. And what you can nicely see, there is a whole number of metastases in the patient. And if you look for the liver, there are multiple PSMA positive liver metastases in the patient. However, if you look to the CT, you already notice that there are changes in the signal, the Hounsfield units in the CT, and there is only very faint uptake in the PSMA, which is also visible on the fusion image. So on the right side, you see the whole body. And again, you see a lot of metastases in the bones and again also, you quite nicely see the liver metastasis.

So this is a patient after all the therapies, according to the current guidelines, who could really benefit from a PSMA therapy. So this is the PET/CT before the therapy and in the upper roll, you see the patient after the first cycle of the PSMA radioligand therapy, was lutetium 177 PSMA, 6 gigabecquerels, in March 22. And this is what you see. This is a cross-sectional section of the liver. So you see the high resolution of the PET/CT, but you see quite nicely in these slices, that there's a very close correspondence of the PSMA positive lesions in the liver in the PET/CT and the SPECT/CT after the therapy.

Oliver Sartor: Bernd, I wonder if I could interrupt you for a curiosity question.

Bernd Krause: Yes, of course.

Oliver Sartor: When you're using the SPECT/CT, how long after the injection of lutetium do you wait before you do the SPECT?

Bernd Krause: So for this SPECT, we used the 48 hours scan, but during our therapies, we do multiple scintigraphies in order to carry out [inaudible 00:05:31], but that's normally 40 out hour SPECT/CT that we perform in the patients.

Oliver Sartor: Right. Yeah. And you clearly have very, very good uptake within a certain segment of the tumors. Yeah. And very nicely correlating with the PSMA PET.

Bernd Krause: Yeah. And if we now look again to the PSMA PET/CTs, so this was the more negative lesion. And so we also clearly see that there is PSMA negativity in the post therapeutic scan. So we suspected that there would be PSMA negative liver metastases in a case of rather advanced disease. And so this for us is irrational to think of more aggressive manifestation of prostate cancer and different target. And so the GRPR receptor, the gastrin-releasing peptide receptor is a target which is known to be expressed on rather aggressive prostate cancer lesions. And therefore, we decided to carry out a gallium 68 RM2 PET/CT and the RM2 is a ligand targeting the GRPR receptor. And I'll show you the results now.

Bernd Krause: So this is the RM2 PET/CT scan. And so you see three things of importance. So first of all, you see RM2 uptake in the metastases that was PSMA negative. Second, you see that many of the bone metastases do not take up RM2. And third, you see a high signal in the pancreas. And so this is a PET/CT scan. The interesting issue about the pancreas, which might make you think about a therapy is that this uptake in the pancreas fades away rather quickly after the PET/CT imaging, so that's not an issue for therapy. But now let's look for the liver lesion and you see exactly this is this axial slice, and this is the huge metastases in the right lower liver lobe with a central necrosis, but with a clear high signal in this metastases.

Bernd Krause: And this again, is the comparative images on the right side, the gallium 68 PSMA PET/CT. And here there's no uptake in this liver lesion. And we do have the RM2 scan here. There are, and this is interesting lesions with co-localizing uptake, many of the bone metastases, however, do not take up at all the RM2. But clearly we see there's high uptake in this PSMA negative liver metastases

Oliver Sartor: Bernd, I wonder if you were to obtain histology, the PSMA PET negative cancers can segregate into several different types. One type might be a small cell and another type might be a more anaplastic, but not small cell. I'm just curious in your experience, not just this case, but have you done biopsies on these PSMA PET negatives and what do you see? I'm just very curious and I think our listeners would also be curious.

Bernd Krause: A very good question. Yes, Oliver, we obtained cytology and histology from lesions and patients. And so there is a clear indication that it's small cell prostate cancer. And so they are often PSMA negative, completely PSMA, negative, these portions of the tumors. There is positive for NSE, neuron-specific enolase, in these tumors. And interestingly, and that's now one of the thoughts we have that it could be neuroendocrine transdifferentiation of the prostate cancer. And this is the idea we have right now for this kind of tumor.

Oliver Sartor: Bernd, it's interesting. I saw a somewhat similar case very recently, and I've actually seen two cases of BRCA2. You made mention in the beginning that he was BRCA2 mutant, I didn't know if that was germline or tumor based genomics, but what we've seen is this emergence of small cell in the context of a BRCA2 mutant that then progresses after initial therapy. So I don't know if this is just a sort of strange confluence cause we have not discussed my observations, but this is quite interesting. Was this patient biopsied? Was this particular patient biopsied?

Bernd Krause: It was not this patient, but it was another patient and this, or other patients and these patients did not have a BRCA mutation.

Oliver Sartor: Interesting.

Bernd Krause: But we didn't have a biopsy here to get histology from this patient.

Oliver Sartor: Well, nevertheless, so I do agree with your transdifferentiation. So we're completely on the same line of thought with regard to the evolution here. So anyway, quite interesting case.

Bernd Krause: Yeah. That's so to speak, a summary slide for the case. So this is a case with PSMA positive lesions in bone and lymph nodes and then the liver with really very high uptake. And therefore these lesions are eligible for a PSMA therapy and the patient and these lesions benefit from the PSMA therapy. However, there is PSMA negative in significant lesions, especially in the liver. We also have observed in other patients lesions outside the liver being RM2 positive and PSMA negative like in lymph node visceral metastases, but also bone metastases. And so therefore this is like a mosaic. So from the same tumor origin, basically there are metastases with different targets expressed on the tumor cells. And therefore these are exactly the patients where in our team and after interdisciplinary discussion, we propose combined therapies, comprising lutetium 177 PSMA RLT, and lutetium 177 RM2 RT in order to be able, really to treat both portions of the tumor.

Oliver Sartor: Very interesting case. And I wonder if you might share how you worked out the dosing schema and did you go with a 7.4 gigabecquerels for the PSMA lutetium? And if so, how did you work out the dosing for the RM2? So I'm just curious how you managed that problem.

Bernd Krause: So we treat the patients according to the VISION protocol. So it's 7.4 gigabecquerels for the lutetium PSMA RLT. For the GRPR targeted therapy, we have a little lower activities so we treat the patients with six gigabecquerels RM2, lutetium led RM2.

Oliver Sartor: And do you use same day treatment? Are you using both on the same day?

Bernd Krause: No, we don't carry out tandem therapies at the present time. So what we do, we alternate the therapies, so we invite the patients for the therapy after six weeks switch, six weeks switch. And so one might, because that sounds attractive, think of tandem therapies, but so we prefer at the present time to do them in an alternate fashion.

Oliver Sartor: Do you have any preliminary results from this patient? Just out of curiosity.

Bernd Krause: We are just underway for the therapy. And so therefore everything is in preparation. And currently we are developing a new GRPR receptor targeted radioligand therapy. And so we hope that especially the therapy, the therapeutic properties of the new rate of pharmaceutical will be optimized. And while you could quite nicely see the quality of RM2 PET/CT is rather high for the lutetium RM2 therapy. For the lutetium 177 RM2 for certain reasons, the serum stability seems not to be that high. So metabolites occur rather around their early after the therapy. And therefore we use now stabilized molecule and this is exactly what this patient is going to receive now.

Oliver Sartor: Couple of questions come to mind. I have looked at some of the dosimetry and SPECT scans post the PSMA lutetium and you see that excellent retention time within the tumor. I mean, I personally have done SPECT a week later and you still have very vivid uptake within the tumors. Do you have any idea about the RMT tumor retention time?

Bernd Krause: Yes. We have carried out a very thorough dosimetry for patients that underwent therapy and we also have done seven day SPECT CTs. So it seems that there is heterogeneity with respect to the patients. So there are patients which show really very good uptake even after a week. And there are others where this is not the case. And it might be that the specific enolase might be responsible for that. So the metabolites are different across different patients. But we have looked at this and again, we do have patients where the optic was still quite strong after one week.

Oliver Sartor: Interesting, but you're looking at even new ligands to be able to further optimize the tumor uptake. So this has applicability of course, to a variety of other tumors. I mean, neuroendocrine prostate is one subset, but I could see, I know there are breast cancers that can do this, a whole wide variety of the neuroendocrine tumors, some of which may not be ideally suited for the somatostatin receptor. So do you envision this in a broad range of tumors and if so, which ones?

Bernd Krause: Yeah. So first of all, I would like to ask you a question because, so seeing these cases, do you also from a clinical perspective, see the potential for this kind of therapy either combined or in a tandem fashion or subsequent? So what is your perspective on prostate cancer in these patients?

Oliver Sartor: Yes, absolutely I see utility. So first of all, the number of patients who have neuroendocrine is a little bit of a complex topic because first of all, it varies in accordance with the pre-treatments. If we go to the older days where androgen deprivation therapy consisted simply of testosterone suppression, then these are pretty rare events. But now that we're using, as in this case, enzalutamide or abiraterone or both, it turns out that the number of patients with a neuroendocrine phenotype is definitely higher. If you look at histology, this may even be as high as in the 40% range, but the type of studies you're doing are really pioneering work because we don't fully understand the extent to which the GRPR receptor will be expressed. So I think through work in your university and others, we'll be able to better answer the question. But is it important in prostate? Yes, it is. But the full magnitude of that importance, I'm still trying to understand. But this is something very important for the future.

Bernd Krause: Thank you. You asked for other tumor entities. Yes, I think there are quite promising results for breast cancer. Also, we are now involved in a upcoming trial in glioma, in brain tumors. It also seems that there might be indication there. And so therefore these are the two entities where I know there's a lot of activity and again, the imaging properties look excellent. So we really have now to go into therapeutic doses and using lutetium 177 labeled radio ligands to look for the kinetics, the biodistribution, and in order to really think of therapies in these tumor entities.

Oliver Sartor: Excellent. And of course, feel like I should ask about the alphas. Have you thought at all, or have any experience with actinium or any of the other alphas with these ligands?

Bernd Krause: So I think there are different alphas. So actinium 225 or lead 212, those are quite interesting radionuclides. I personally think and this is also the duration that we followed that rather than using another radionuclides for PSMA negative prostate cancer patients, we use other radio pharmaceuticals addressing or targeting other targets. But there is I think, great potential for alphas because depending on the tumor configuration, there might be an even higher response. Again, I think the research is going on. We do not have a lot of experience with alpha emitters for the therapy, but we have to be cautious because there are severe side effects for these alpha therapies.

Oliver Sartor: Well, this has been a very interesting discussion. And one of the things that I might mention for our listeners is that UCLA did a series in which they treated essentially all PSMA PET positive tumors, without exclusion of the PSMA PET negative tumors in a series of patients. They recently reported that these individuals who have CT scan evidence of tumors that are PSMA PET negative do very poorly. So I applaud your innovative approach to this setting and certainly wish your patient will.

Bernd Krause: Yeah, I just can confirm this is also one of the approaches that we choose and for the GRPR. This really opens a new opportunity. But for small cell cancer variants of prostate cancer indeed, the prognosis for the patients is rather poor. That's also what we observe in the patients that we treat.

Oliver Sartor: Yeah. These are tough patients. No question about it.

Bernd Krause: Oliver, thank you very much for this intense discussion of the case. It was really a pleasure to go through the case and really to look for perspective and new options for prostate cancer patients. I think it's obvious that lutetium 177 PSMA is really a blockbuster in the therapy of castration resistant prostate cancer patients, but we know there are PSMA negative patients. And so there are now options targeting other targets in these tumors to be of help for this patient group. Thank you very much.

Oliver Sartor: Well, thank you. Thank you for the opportunity to be here today. And again, I think you've highlighted a very important point about the heterogeneity of these patients and newer approaches. So congratulations for your investigations and we look forward to hearing more when the time is right.

Bernd Krause: Thank you.

Oliver Sartor: Thank you.