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Alicia Morgans: Hi, I am so excited to be here at ASCO GU 2024 where I have the privilege of speaking with Dr. Boris Hadaschik from Essen, Germany. Thank you so much for being here with me today.

Boris Hadaschik: Oh, thank you for the invitation, Alicia.

Alicia Morgans: Well, wonderful. You had a wonderful presentation on PRIMORDIUM, which is some data that is coming out of a trial that we are expecting to see from a disease control standpoint in the future, but really presenting some imaging data from this study. Tell me a little bit about what the PRIMORDIUM trial is and tell me a bit about some of the imaging that you were able to present.

Boris Hadaschik: Yeah, certainly. So, PRIMORDIUM is an ongoing phase three trial that looks at patients with high-risk biochemical recurrence post-prostatectomy. And in these men, it is tested that for the subgroup which has a local PSMA-PET-positive signal in the pelvis with allowed metastasis. The hypothesis is that the addition of six months of apalutamide to six months of ADT improves metastasis-free survival. But PRIMORDIUM is the first study to really deeply integrate PET imaging because it's not only used for baseline scanning but also our primary endpoint, MFS, is PET-based. So, we are looking at new distant metastasis on PET and the PET imaging until that timeframe is blinded and with central review. But then if we see one more distant metastasis, then it's certainly unblinded to give the patient the option of a second local curative attempt.

And the radiotherapy part for these men with high-risk biochemical recurrence is predefined. So, we do radiotherapy for men with localized PSMA-PET-positive disease, not only to the prostate bed but also to the pelvic lymph nodes. So, we do intensified local therapy plus then the randomized addition of apalutamide and it is intensive therapy. And so we had some trouble, to be honest, with the recruitment of the trial. We are now halfway through, so 200 men are recruited, and we also integrated because it was four or five years ago when we designed the trial, unknown about the kind of biologic importance of being PSMA-positive or -negative. So, for the PSMA-negative patients, we included an observational cohort. And now, what we are presenting at this year at ASCO GU are the baseline characteristics of the ongoing trial, where we compare those men with PSMA-PET-positive disease versus PSMA-PET-negative disease to be able to find out whether there are biologic differences or not.

And to make the long story short, we don't see big biologic differences. The main separator is PSA level. So, PSMA-negative patients had a median PSA of 0.3, and PSMA-positive patients had a median PSA of 0.5. And also, looking at the time since radical prostatectomy, there was a 10-month difference. So, if we waited for 10 more months, then the likelihood of a positive PSMA-PET is bigger. So now, we are implementing amendment three of PRIMORDIUM too, because we've seen that there are no biologic differences, these are all men with high risk. We can, so now we make the trial a little more pragmatic because now we will allow for the randomization also men with PSMA-negative disease. And so this trial is more pragmatic to be able to push it over the finishing line to find out whether intensified ADT for a limited amount of time, six months, is better than not intensified ADT.

And if you look at the current presentations and the formula 509, for example, I mean, we believe that this will become a positive trial. And for myself, being heavily invested in imaging and novel imaging, I'm really happy and thankful to Janssen, which is sponsoring the trial, that they really committed to speaking to IMA at that time to have PSMA-PET really as a primary endpoint.

And this trial, to be honest, is kind of the basis. There's now a similar trial with FDA approval from Bayer, ARASTEP trial, but they have two years of intensified treatment but also a PET-based primary endpoint. So, I think that the field is moving, and we have to really embrace novel imaging because it's just more accurate. But certainly, we are fully aware that we now have to collect data within clinical trials whether PET imaging really correlates with hard oncologic endpoints, because we know MFS on conventional imaging is a surrogate or earlier signal for OS, but we don't know that yet for PSMA-PET imaging. So, I think academically it's a very interesting trial. Clinically, I think it has a likelihood of success because we are focusing on high-risk recurrence. And then, yeah, we have to see and hear. This post was the foundation for now amendment three to make it more pragmatic.

Alicia Morgans: Fantastic. And it sounds like this is actually in combination with salvage radiation to the pelvis, right? And so, I think it's wonderful that you're opening up to patients who are PET-negative because if it's really the case that the average PSA is 0.3 versus 0.5, we know that we want to actually give our salvage radiation at a lower PSA than 0.5 whenever possible. So, if the median's 0.5, that means that a fair number of patients are going to be over that. We have a much greater likelihood of curing those patients with the PSA that's closer to a median of 0.3 and hopefully even lower. So, I think it's pragmatic. It will help, hopefully, with feasibility and enrollment, but also may help to cure more of these patients. So, really important work that you're doing.

As you think about this metastasis-free survival endpoint by PSMA-PET, I would love to hear your thoughts on how we can judge that when we have some patients who have a PSMA-PET that's going to be positive at baseline, some will get metastasis-directed therapy, some may not, and then a PSMA-PET that's negative at baseline. And how do we use that information and then actually judge progression by a PSMA-PET at the time of potential metastasis? And I know this is a challenging question, but you are a urologist always up for the challenge. So, tell me about that, please.

Boris Hadaschik: Yeah, thank you for the really excellent question, which is not perfectly easy to answer, but there are a couple of points that I want to stress. So, the first thing, it is good that we have a baseline PET. So, we have a baseline PET, and then we repeat PET imaging throughout the trial within the context of the trial, and so we can gather a lot of information. And we have expert readers to look at the PET scans, and you also have to use the same tracer every time so that there is little variation. So, your concern is certainly valid: there are some patients that might be PSMA-negative despite having metastasis on conventional imaging at some point in time. But the amount of hormone-sensitive prostate cancer that is primarily PSMA-negative is like 5% to 10% max. So, this is a reasonably low number of patients. This is point one.

Then the other point is that we know where we did SBRT. So because SBRT is, you have to stratify for it in the beginning. So, the investigator has to say, "If there is something distant, I will do SBRT or not." But in our here-and-now baseline characteristics, we saw only 10% of men with disc metastases in the PSMA-positive fraction. So this, again, is a relatively low known number. And the main challenge of the trial is that there are no really established criteria to define PSMA-PET progression. So, it is something that the prostate cancer working group criteria are now discussing. But I believe they will not come up with a clear-cut suggestion because there's no data yet. They will just suggest what to collect. And in fact, we right now have ongoing a global consensus to try to define a clinically applicable model.

But so far for PRIMORDIUM, we used criteria that in a small consensus we developed, and I think having multiple PET scans to compare makes it rather easy to define a new distant metastasis on PET. But whether that correlates with conventional MFS and overall survival remains to be seen. But certainly, as secondary endpoints, we both have conventional MFS, so we strongly encourage continuing conventional imaging. And we have endpoints like overall survival, but I mean this is years, years, years down the line. So, it is a risk that Janssen was willing to take. And so I'm very appreciative of that. But we don't know yet whether our definition of PET-based MFS will hold over the next decades or not, but it's a starting point, and we collect the data.

And also for other now trials in localized therapy, because you have now in the US this very broad possibility to use PET. So, every trial in a localized or in a curative setting has to now implement PET and decide what to do with it. And I think it's good because it's accurate and more specific, and it will be helpful. But we have to be patient to see whether it really is a proxy or an earlier surrogate for hard oncologic endpoints.

Alicia Morgans: I think that's such a great discussion of the challenges, but I really applaud you and the team for being so innovative in incorporating this. When we look at clinical practice, we see that PET scans are being used, and if we choose to ignore that in our clinical trials, I think it is to our peril to do that. So, I think it's wonderful that you're doing this. I truly look forward to seeing those scans over time, to seeing your PET scan MFS endpoint. And it's also fantastic that you have conventional imaging in that study as well and in that follow-up as well so that we'll have the crosswalk, we'll have the understanding, and we'll go from there. I'd love to hear, is there anything else from the findings that you presented at GU ASCO that you wanted to share? I think all the work that you and the team have done, really incredible to help us define and understand that subgroup of patients with high-risk biochemical recurrence as you've included in this trial.

Boris Hadaschik: No, I think the most important point is that we don't see biologic differences between the PET-negative and PET-positive cohorts. And I strongly support your comment that, right now, we really should not delay salvage radiotherapy in a curative intent just to wait until PET becomes positive. So, now having good and predefined localized therapy, plus the addition of intensified systemic therapy for a limited amount of time, I think this is going to be the future and I'm happy or hopeful that we can really prove its use. And so, it's a privilege being involved here.

Alicia Morgans: Wonderful. Well, I so appreciate you talking this through. Congratulations on this presentation and certainly congratulations on the PRIMORDIUM trial in progress. I'm hopeful that it changes our standards of care and that it gives new opportunities to cure some patients who have recurrent prostate cancer. Thank you so much for your time.

Boris Hadaschik: Thank you for the invitation.