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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with you today. A real pleasure to be able to have Wolfgang Fendler, who is the vice chair of Nuclear Medicine at Essen, longtime leader in the theranostic field, join us today. And we're going to be talking a little bit about PSMA as a response, a predictor, and a response effector. And how do we evaluate these important scans with regard to not only response, but progression? And Wolfgang, I'm going to really look forward to what you have to say.

Wolfgang Fendler: Thank you very much, Oliver. Thank you very much for the kind introduction. I have a few slides. This is a really exciting and interesting, and also very timely and important topic, response and progression criteria using PSMA PET. How do we image prostate cancer outcomes in the future? And I have prepared some of the current evidence, but also opinions on how to possibly do this.

I think one of the general questions is, if we have this new modern imaging technology, is more disease on this next generation imaging, on PSMA PET, is more disease also equivalent to worse outcome? It's not a trivial question, if you think about a very sensitive imaging modality.

And we have conducted a multicenter trial, which was published in Lancet Oncology, that really looked into this, and could nicely show that if you see more disease in a cohort-based setting, if you see in a large cohort of patients, patients with more disease, of course, patients will also be worse off in terms of their overall survival, and would have a higher risk for shorter survival in the entire cohort. And if you look at the—these are univariate analyses and hazards with association with overall survival.

And if you look into some of the really interesting variables, like tumor volume or number of tumor lesions that you can depict on PSMA PET, it really seems that the tumor load—that's the amount of tumor that we detect on PSMA PET—is associated with patient outcomes. So there seems to be a basis. A prerequisite seems to be fulfilled to use PSMA PET also as a response assessment tool if we monitor disease load on PSMA PET.

And we try to make a suggestion on how to standardize reporting and also standardize response assessment using PSMA PET, which was done here. There are many systems, but we tried to propose this as the PROMISE criteria published in European Urology.

And just to summarize the response assessment part, one of the suggestions was to use two sets of criteria for response assessment. One would be called the PPP criteria for limited disease or more in the hormone-sensitive disease space. And on the other hand, to use the RECIP criteria for more advanced disease stages. So metastatic disease or castration-resistant disease. And I'm going to introduce those two criteria to you in the next slides.

The PPP criteria are bound to the tumor lesions. So they depict the tumor load by a number of lesions. And this has been an expert consensus proposed by a group around Stefano Fanti in 2020. And they included PSMA PET findings, also CT and MRI findings, but also clinical findings to make a distinction between progressive disease and non-progressive disease.

And this is what I call the so-called basic PPP criteria. Very simple. If there is no new lesion on PET, then you would not call the disease progressive disease. If there's one new lesion on PET, you might call the scan progressive disease, depending on what other findings you find. And if there are two or more new lesions on PSMA PET, you would call it progressive disease.

This is the basic assumption around PPP criteria. And of course, there's also an advanced part that looks into not only PSMA PET but also takes into account conventional imaging, also biopsy, also change in size, change in volume, which I'm not going to go into detail. But these sentences, these detailed criteria try to make a distinction between progressive disease and non-progressive disease. But this all is focused on the number of lesions and appearance of new lesions on the scan.

In contrast to this, for more advanced stage disease, for metastatic castration-resistant prostate cancer, for high-volume disease, the so-called RECIP criteria have been proposed. And these are more focused on tumor volume. So they look into a change in the entire tumor volume and, in addition to that, the appearance of new lesions.

So the definition—the central definitions here are—partial response would be defined as a decrease in PSMA PET-depicted tumor volume by 30% or more without appearance of new lesions. And progressive disease was defined as 20% increase with appearance of new lesions. These are the two center definitions. And then, of course, depending on other findings, you can also define complete response by complete resolution, or all other scenarios would be called stable disease for the patients.

And there has been evidence—in contrast to PPP, there has been solid evidence on the proposal of those RECIP criteria in the setting of a PSMA-directed treatment in patients with metastatic castration-resistant prostate cancer, where the RECIP category, PSMA PET response by RECIP, has been associated with overall survival. So patients with partial response lived longer as compared to patients with progressive disease by RECIP criteria.

There are some software tools that can help in the future to make a standardized assessment of PSMA PET, but also standardized response assessment using those two criteria. This is one software tool that the University of Essen has worked on with an academic collaborator. This tool is called ePROMISE. And by a few clicks, you can really enter and generate a standardized finding on PSMA PET using PROMISE criteria.

And by entering the tumor volume and the number of new lesions, you can also make a distinction between progressive disease versus non-progressive disease by both PPP and RECIP criteria. And this is supposed to be a simple and easy tool to be used on PC, Mac, or any other platform, both mobile and local installation.

So I would like to summarize. There are response assessment criteria that have been proposed and standardized reporting that have been proposed. I just introduced two criteria that have been out there for some time, which are the PPP, the progression criteria, and the RECIP criteria. One is more for the number of lesions. The other one is for tumor volume.

There are currently efforts by PCWG4 Groups and by the European SPARC Group to, again, simplify this and to make proposals for future response definitions using PSMA PET. And overall, of course, this is true. More evidence is needed. And there's one ongoing registry study from our department that tries to really get everyone on board to generate as much evidence as possible in the future, to define response criteria, and also define risk groups on PSMA PET. And this might really make a difference and generate the evidence that we need in the future. Thank you very much, and really looking forward to discuss these topics.

Oliver Sartor: Thanks so much, Wolfgang. It's really a provocative topic right now. We're entering this brave new world, where conventional imaging is becoming somewhat passé. And even in our clinical practice, we are not using nearly the CAT scan and bone scans that once were our staple. And there are a lot of questions around these points.

I like your division into more of the argument of static, early stage and the later stage. And the total tumor volume looks like it's really going to be a nice path forward. And we all agree that the amount of the tumor makes a difference to the patients and their outcomes. So thank you for delineating and quantifying that.

Now, one of the things that came to mind is that not all lesions are PSMA positive. And I just wanted to hear your thoughts about how we might incorporate those aberrant lesions, maybe they're neuroendocrine, maybe they're anaplastic, undifferentiated, non-PSMA-producing lesions. How do we deal with those and the concepts in the PSMA era?

Wolfgang Fendler: I think to differentiate a lesion or neuroendocrine differentiation or loss of PSMA expression by itself is indicative of high risk for a patient. Luckily for us, fortunately for PSMA imaging, a solid number of prostate cancers are really PSMA positive, say, more than 80%, 90% are PSMA positive, and can be really nicely depicted on PET.

And I think whenever the tumor becomes negative or is a fast-growing neuroendocrine prostate cancer that is, per se, PSMA negative, that's really a large risk factor by itself for outcome. And then the question is, how do we determine response for those types of cancers? In the future, looking from the eyes of molecular imaging, I would really propose to you to go back to FDG-PET imaging on those patients because I really think that this is the molecular entity that can deliver us both stratification and metabolic response assessment in the future. But just as a proposal, to really reinstate FDG-PET for those tumors that are PSMA negative.

Oliver Sartor: I was going to raise the—I'm going to call it the Australian argument. There are those from Australia who want the dual FDG-PSMA PET in everyone. And yet, at least in the United States, there's some significant financial barriers to that because we just don't reimburse for two PETs. We get one PET. We can't get two PETs. So it's been a bit of a logistical issue. But this is important to consider as well.

But nevertheless, it looks like the total tumor volume is going to be holding up quite well. Are you using total tumor volume in your decision-making today about administration of radioligand? I mean, if you see somebody who's responding by PSMA PET criteria, are you potentially using adaptive dosing? That's one question. So we'll stop there. Adaptive dosing, for those with good responses, is that part of your current criteria? Or how do you determine these changes, and translating that into clinical action?

Wolfgang Fendler: We really use the PPP and RECIP criteria in our clinical practice. So baseline assessment is really bound to the vision criteria that have been proposed to make an indication for PSMA treatment. And then once patients undergo PSMA-directed treatment, we rescan them using PSMA PET after every two cycles. It can also be three cycles. Could also be four cycles. But I think it should be after two or three cycles.

And then for those follow-up PETs, we really determine PPP criteria, RECIP criteria, in addition to PSA level, the clinical status of the patient, and AP level if there's bone-dominant disease. And then we take all of these categories and response assessments into account to make a decision, whether we continue treatment or whether we would stop treatment after the given number of cycles.

Adaptive dosing is not so much something that we do currently in the clinical practice, also for logistic reasons. Because it's still bound to a fixed dosing that we do. Adaptive dosing is really something that we would rather use to react to adverse events. If there should be—if there would be any decrease in blood counts or renal function, we might go down in the dosing. Otherwise, for us, the question really is should we continue treatment in the way we do it? Or is there a reason to stop because there's just progressive disease or non-response?

Oliver Sartor: So two questions immediately come to mind. What about SPECT scans? It's pretty easy to get SPECT scans after lutetium administration. Some people do it routinely, some don't. Do you think that SPECT will be able to play this role, or do we need the PET or do we need both? Or how do you approach those SPECT/PET question?

Wolfgang Fendler: The way I see it is that we have a broad panel of good or, let's say, small molecular PSMA imaging modalities. And to these modalities, we have PET/CT and PET, which is really the major modality. But we also have SPECT/CT, intra-therapeutic, post-therapeutic SPECT imaging. We might have, in the future, also technetium PSMA imaging.

I believe all of these are very good imaging and spatial biomarkers for prostate cancer. And of course, you have the premium version, which is the PET/CT, high resolution, goes fast, quantifiable. And you have the feasibility versions, which is SPECT/CT. But I still believe they are all spatial imaging biomarkers bound to the molecular signature, bound to the PSMA expression level.

And the current data indicate that the SPECT/CT, the intra-therapeutic, can just as well delineate the tumor load under treatment. And changes of this tumor load also on SPECT/CT will give us very good indications, whether the patient is going to respond or not. And that's really the beauty of this type of treatment. We get therapy and imaging all at once.

Oliver Sartor: Yes, it's very nice. So going back, if you're routinely, for your radioligand therapies, getting the PET scans about every other cycle, and you start seeing that total tumor volume increase by 20%. Is that a stop signal? Is it time to change therapy? Then, how do you handle that in your practice?

Wolfgang Fendler: That's really looking at the RECIP criteria. An increase of 20% and seeing new lesions, that is really a RECIP progressive disease, and that's a red flag for us. So continuing that treatment, we would really have to get good arguments at hand. One of those would be if the patient responds clinically very well and just feels very well, we would give them another chance and continue treatment.

Most of the times, we see an increasing tumor load. We also see an association to that increase in PSA level, maybe also deterioration of clinical status. And then it's really clear to stop treatment and not continue. I believe if the imaging plus one other factor indicates disease progression, there is no good clinical reason to continue a treatment because you might do more harm by toxicity than benefit because the tumor is just not responding.

Oliver Sartor: Yes, absolutely. Last question is going to be a little bit difficult. Because as you and I are talking today, we're talking about clinical practice. And I think we're both evolving in a similar way. But we have the regulators. We have those who will regulate drugs in the USA and Europe. And they've been a little more reluctant to incorporate the PSMA PET as a criteria for response and progression in regulatory approval trials. What will it take—here's the hard question—what will it take, do you think, in order to demonstrate to the regulators that this is a valid endpoint for both response and progression?

Wolfgang Fendler: So I believe what it will take is implementing PSMA PET in prospective clinical trial designs, could be phase 2, ideally phase 3, and showing that increase in disease by new lesions or increase in volume is going to be associated—so the imaging progression is going to be associated with shorter overall survival. It's really making a link between our early imaging biomarker and then the late cancer outcome that is most significant for most drug approvals, which is overall survival. I think this is what it will really take.

And I believe that the current approach is really ongoing. The PRIMORDIUM trial and the ARASTEP trial have both implemented PSMA PET imaging, also as an endpoint, including progression criteria by PSMA PET. So if there's a new lesion seen on the follow-up PSMA PET, this would be called PSMA PET progression, and would count as an endpoint.

And I think these two trials would deliver us—would be the first ones to deliver us association between PET endpoints and later overall survival, and also PET endpoints and conventional imaging endpoints. And I think that's really what the FDA needs.

Oliver Sartor: Terrific. Wolfgang, I wanted to thank you for being on here today. You have a great perspective and a huge amount of experience in this area. Wanted to thank you for sharing your experience, sharing your data, sharing your thoughts.

It's a rapidly moving field, and you're one of the leaders. We look forward to your continued leadership and look forward to your contributions not only in this area, but in many areas of RLT. So thank you.

Wolfgang Fendler: Thank you very much. It's really been a pleasure to discuss these topics. Really important. Thank you.