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Alicia Morgans: Hi. I'm so excited to be here with Professor Boris Hadaschik, who is joining me today from Essen, Germany, where he is the head of urology there. Thank you so much for being here with me today.

Boris Hadaschik: Thank you very much for the kind introduction. It's a pleasure being here.

Alicia Morgans: Wonderful. Well, so excited to talk with you about a presentation that you and your team gave at ASCO 2023, where we really consider the implications and some longer term outcomes of the use of PSMA PET in a non-metastatic castration-resistant prostate cancer population, and what that means for us as clinicians, as this technology is increasingly used. Can you tell us a little bit about what you investigated?

Boris Hadaschik: Certainly. In 2019, we published a dataset of 200 men with high risk non-metastatic CRPC on conventional imaging, and in that publication we're able to show that if you use more sensitive imaging, there is a lot of upstaging. So, 55% of these 200 men, in fact, had disc metastases on PSMA PET. Then we looked whether this novel imaging really was able to help us deciding if a patient needed more intensified treatment or not, because then we looked at individual data from the SPARTAN study, where apalutamide was tested in men with high risk CRPC, and using risk factors for disc metastases on PET, we were not able to see a clear patient subgroup that did not benefit from apalutamide.

If you asked me, "Is PSMA PET the most useful exam in men with high risk CRPC?" No, it clearly is not, because it did not have clinical consequence. Nonetheless, we are at present at a breaking point where we have conventional imaging that is suboptimal, and now we have approved PSMA PET tracers, and you in the US, you have a very broad possibility to use PET for various reasons.

In Europe, we are a little bit more restrictive, and there's certainly also financial toxicity, so we have to learn when to use PET in the best places. And at present, our guidelines in Europe, they state, "Yes, you can use PSMA PET, but we have to be very, very careful how to act on it, because it has not been integrated in the big clinical studies."Also, we are being criticized because we don't have data correlating PET with hard oncologic outcome.

So here now we went back to these 200 men that have been identified prior in this international group, and in these 200 men, we now ask the question, "What happened? What is subsequent treatment after PET? And what is the outcome looking at overall survival?" And we found out that PSMA PET, at time of high risk CRPC without metastases on conventional imaging, so a select group of patients, but in these men, if you have a PSMA PET that shows more than five disc metastases, these men are at increased risk of dying of the disease, so their overall survival was much shorter than men without or with less than five disc metastases.

Similarly, PSMA PET provided additional biologic information of aggressiveness, because if there was a high SUV on the PSMA PET, so if the tumors lit up brightly on imaging, these men were at higher risk of dying again of the disease. So we believe that we have identified some prognostic factors that are useful for further development and testing in clinical trials, so that we can identify groups of patients where we have to more intensify treatment, and other groups where we maybe can learn we can deintensify or more use targeted therapy.

So we also asked the question, in this group of men that were treated before the approval of apalutamide, enzalutamide and darolutamate in the disease setting, what happened? And clearly, if men had local recurrence only or oligo metastases, there was local treatment, either conventional salvage radiotherapy or SBRT to this metastases, and if men had polymetastatic disease, despite not being approved at that time, Anderson signaling inhibition was used and the outcome of the men altogether was quite favorable. It was comparable to the treatment arms of the studies, for example, such as SPARTAN.

So it's not rocket science. It's not science. It's nothing really, really new practice changing right now, but it gives us confidence to say that, yes, PSMA PET is something you can act on and it will help us to more clearly understand our patient populations for further trial development.

Alicia Morgans: I think it's also really important that in this population, in this cohort, as you said, you've been following for a long period of time, if you had a PSMA PET positive patient with more distant metastatic disease and those patients were intensified, this is almost like a real world application and cohort study of the clinical trials that we know led to approval of these agents. And so you're really suggesting that, in this real world population, despite having PSMA PET avid disease, which was really unknown prospectively in those trials, you are able to achieve similar outcomes, right?

Boris Hadaschik: That is correct. High risk M0 CRPC is a mixed bag of patients.

Alicia Morgans: Yes.

Boris Hadaschik: And I think this niche indication was useful for designing trials and getting approval of these drugs in that disease space. But if you use more sensitive imaging, there clearly is a differentiation between men that have metastases and men that are in an intermediate stage, and you maybe can salvage a few of them, even with curative intent.

Alicia Morgans: So let's dig into that a little bit more. Again, this was non-randomized. This was really patients treated through the discretion of the treating team. But I would say that probably, the discretion of the treating team is very similar to what we're doing these days.

PSMA PET identified lesions that were still in the pelvis or maybe in the prostate itself. If that prostate had not previously been radiated, radiation was delivered as salvage radiation, or local SBRT might have been used. In this population, you didn't necessarily comment, at least earlier, on the use of intensified systemic therapy, but you did say that those patients seem to have a similar positive outcome as compared to those patients who had intensified systemic therapy.

Again, in this non-randomized cohort, for those patients who had intensified locally directed therapy, you seem to achieve really good outcomes. Is that what you found?

Boris Hadaschik: Yes. I think that reflects nicely what we believe we found, but at this time in ASCO, I'm still battling with myself what to do with data such as now piece one. If you have men with low volume disease, how intensified do we have to treat? Can we define populations where maybe finite intensified treatment duration would be nice?

And then Wolfgang Fendler, who is co-author of the work that I just presented, he also showed another paper where we learned that bone scans, they are false positive sometimes in this oligometastatic hormone sensitive disease space. I think it is, at this point, very difficult for me to speak with a patient, if he has oligometastatic disease, how much we have to intensify.

We all know that now for metastatic hormone sensitive disease, at least to double it is standard of care; and we know from Stampede that if you use only ADT, that local radiotherapy is certainly beneficial, but that was without metastasis directed therapy, so we don't know yet how useful that is.

And now that piece showed that probably a quadruplet is too much. So it is really very interesting times, and I truly believe that if we integrate biomarkers and more sensitive imaging, we can more clearly dissect out which patients need how much treatment, because all treatments do cause adverse events.

It is great to see what we have achieved over the last decade with prostate cancer, but there's still another decade to go to really try to find out how to treat the individual patient.

Alicia Morgans: I have a feeling that even within that decade, the more answers we find, the more questions we will unearth, too. But I wonder, could you give just a recommendation or guidance to clinicians who are eager to think about your findings and think about how they may come into play in their practice?

Boris Hadaschik: I think our findings show that PSMA PET provides valuable information, and if you ask me what is the best time point to use PSMA PET, it is clearly all men with biochemical recurrence after local treatment. That's clear because you can improve on salvage therapy and know where you are with that patient.

I also truly believe that, for primary staging and hormone sensitive disease, it adds value, because the proPSMA study and Wolfgang Fendler study just now at ASCO showed that it is not only more sensitive, but more specific. So we have a higher accuracy to again, tailor treatment to our patients.

And then the third indication that clearly is an excellent spot for PSMA PET imaging is to assess eligibility for lutetium PSMA radioligand therapy. So at time just now, if you have metastases, metastatic castration-resistant disease post one line of AR targeted agent and post one line of chemotherapy. But again, this might change and lutetium PSMA might move earlier.

So I think yes, you should embrace PSMA PET, use it early, use before radioligand therapy, and all in between is more academia driven. We can learn, we have to assess maybe it is helpful for response assessment, provide signals early if a therapy is working or if we might have to intensify it, or if we can deintensify. It is an interesting interplay, and I believe that is this just an important piece of the puzzle. It is not perfect. It's far from being perfect if you compare it to a microscopic assessment of a lymph node. We are not that sensitive. But it is clearly better than conventional imaging with the only caveat that conventional imaging is the basis for all clinical trials.

Alicia Morgans: So with each advance we find challenges, and a PSMA PET is not a microscope. It can only detect to the limit of its ability, but use of it across the spectrum where it's indicated now, and perhaps in those gray areas in the future when we have that data, we'll continue to, I think, improve the outcomes of patients with prostate cancer. So thank you so much for your time and for your expertise today.

Boris Hadaschik: Thank you for having me.