Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joining UroToday for a discussion with Dr. Piet Ost, who is a radiation oncologist in Belgium. Piet, thanks so much for joining us today.

Piet Ost: Thank you, Zach. Happy to be here and joining UroToday for a discussion on a topic very dear to my heart. So I'm a radiation oncologist, as you said, based in Belgium. I clinically work in Antwerp, and a lot of my research is still connected to Ghent University.

Zachary Klaassen: Fantastic. So we've been doing a series on ESTRO 2024, covering some of the key data, and certainly your presentation on STORM and PEACE V fits that criteria. So maybe just walk us through the rationale, maybe the genesis, for the STORM Trial.

Piet Ost: Yeah, happy to provide some background because it was an interesting step-by-step process, actually. So when we started off thinking about oligometastatic disease, it takes us back now more than a decade. We started off with choline PET/CT, which became very popular in Europe, less popular in the US. So a lot of centers started to have choline, and especially our center was a popular referral center, but we started looking into patients with biochemical recurrence and mapping where these actually occur. We were one of the first to indicate that the majority of patients with a biochemical relapse following local therapy actually relapsed in the nodes. So this was a new clinical situation that we didn't know how to handle. And as the years moved forward, I reached out to many centers in Europe to see, "Okay, how do you approach a patient like this?"

And I got two different answers: one being elective nodal radiotherapy, the other being SBRT. Some were throwing in some systemic therapy, others said, "No, we don't do that." And I kept on discussing and thinking of a trial, and the first step was I had one of my PhD students collect retrospectively our own data, which was mainly SBRT, and compared that with other groups in Europe. We came up with a comparison that indicated that elective nodal radiotherapy actually improved outcomes. So that was the start of me thinking, "Okay, maybe we should do a randomized trial then to prove this is actually better." And in discussing with Thomas Zilli, our colleague from Switzerland, he actually also came up with a design like that. So at a meeting, we were both presenting the same concept for a trial.

So then we put our heads together and said, "Okay, your trial is called Alpha MET, mine was called TORON. Let's make something which is maybe more appealing, get a better brand, and let's just collaborate together." And that was the start then of the STORM trial, where we said, "Let's compare stereotactic body, so focusing on the lesion only, with elective nodal radiotherapy." We discussed systemic therapy a lot, but we saw the move towards integrating at least for a part or a temporary duration, androgen-deprivation therapy. And that is what we came up with then, that in following what we've been doing with salvage radiotherapy, it would make sense to at least add six months of ADT. So that led up to the design of the trial, and that's a bit of background.

And then throughout Europe, even Australia, we found different collaborators that were very, very much interested. We found some funding to run this trial, all nonprofit organizations. And as you can see from the slide, we decided to allow both choline and PSMA as a tracer because simply both were still very, very prevalent in Europe. And throughout the trial, you can clearly see everybody switched to PSMA. So that's why 80% in our trial are actually PSMA screens.

And for the metastasis-directed therapy, we discussed a lot with our radiation oncology colleagues who said, "Yeah, SBRT is the approach." But we also had urology colleagues who said, "No, we do a salvage lymph node dissection, and often we go for the region of the node, we don’t always do a bilateral one." And I said, "Okay, then a form of salvage lymph node dissection actually is also metastasis-directed therapy because you're unable to clear all the nodes." So we allowed that as metastasis-directed therapy because salvage lymph node dissection also didn't have any evidence. So we grouped that in our Arm A as metastasis-directed therapy with six months of ADT and compared that to Arm B, where that was salvage lymph node dissection plus elective nodal radiotherapy. Or when radiotherapy was chosen, we allowed for a focal boost. You could see that as elective nodal plus an increase in the dose. That's a bit of that concept. And again, with six months of ADT.

So we actually wanted to see, do we prevent new relapses in that pelvis because that was the main message that came from our retrospective analysis, that if you focus totally on what you see on imaging, which was mainly choline, you do miss microscopic disease and your patient will relapse again in a neighboring node, which gives you some trouble because you have to repeat your imaging, repeat your treatment. So repeat metastasis-directed therapy might create some anxiety, might increase toxicity in the long run. While with elective nodal radiotherapy, you go for the entire pelvis at once.

So that made us discuss, "Okay, what is a fair endpoint then?" And we had a lot of discussion back and forth, and we thought, "Well, a meaningful endpoint, if you look at a surrogate for survival, is metastasis-free survival, mainly a surrogacy that was proven in the earlier setting in localized disease." But nevertheless, we thought, "Let's use metastasis-free survival as the primary endpoint. And in the MDT arm, we do allow repeated MDTs. So if a patient recurs in the pelvis, you can repeat your SBRT and see if the time to metastasis is different." That was our primary endpoint.

Zachary Klaassen: That's great. And before we get into the results that you presented at ESTRO 2024, maybe walk us through some of the pre-presentation data that's been presented. I know you did three-month initial sort of acute toxicity, and then at EAU, which was just before ESTRO, you guys presented longer-term toxicity data. Maybe just walk our listeners through that data.

Piet Ost: Yeah. So the main two focus points of toxicity are, of course, urinary toxicity and rectal toxicity. And what was presented at the EAU, the longer-term, the two years, we actually didn't see a lot of difference between both arms. If you look at the rectal or gastrointestinal toxicity, we were in the range of 5% to 6% in both arms, very comparable between groups, which was surprisingly low. I must admit that even in the long-term, the toxicity we did see was fairly mild and temporary, which was also interesting to see.

However, for the urinary toxicity, we do also end up with around 22% to 26% of grade two or higher GU complaints, which was a bit high, in my opinion, if we were thinking about SBRT as a focal therapy because often these nodes, the relapses, are not close to the bladder. Then we were thinking, "Okay, why is this?" Well, if you look at the patients being included, most patients actually had radical prostatectomy as their primary treatment. Some had salvage prostate bed radiotherapy, but the majority did not. So in the trial, we did allow salvage prostate bed radiotherapy to also be performed in case the referring physician thought that was something that should be done even though the PET could be negative in that area. So we looked a bit more into detail, and what we saw was quite striking that if a patient got randomized to MDT, the majority of physicians did not do salvage prostate bed radiotherapy. They often abandoned that.

While in the elective nodal radiotherapy, a lot of physicians said, "Yeah, we're treating in 25 fractions anyway. Let's include the prostate bed because it's so close by, it's easy to irradiate and support." So that is probably why in both arms we do see a bit of GU toxicity because in both arms the prostate bed was included in 20% to 30% of our patients. And if we looked at it from a logistic regression perspective, indeed the odds of developing grade two or higher toxicity are doubled if you include your prostate bed. So that is very interesting to take into account. It is mainly the prostate bed, so the proximity of the bladder that causes our GU toxicity. It is not including big parts of the pelvis. It is probably that bladder neck, which we know causes harm in 20% to 25% of our patients.

Zachary Klaassen: I like the fact that you guys have a number for that. I think the odds ratio is 2.16, so we can tell our patients if we [inaudible 00:09:41] prostate bed, it's nice to have a number to give them because oftentimes we say, "Yeah, we think this is why it's causing it." But I know it's sort of a different point in the study, but certainly an important number, I think.

All right, so let's dig into the data for the efficacy outcomes which you guys presented at ESTRO. So the first one here is biochemical recurrence-free survival. So walk our listeners through this data.

Piet Ost: Yeah. So this is the first endpoint that always reads out. This is the time to a PSA recurrence, which clearly here is in favor of the elective nodal radiotherapy, where our median for the SBRT is around 30 months, a bit higher, but our three-year rate is 47% as compared to elective nodal radiotherapy where you get 69%. So there's a 22% difference in the biochemical relapse-free survival, which is quite high. So that means that if you discuss both options with your patients, you can at least tell them, "If we go for the entire pelvis, we are able to render you PSA-relapse free for a longer duration of time." And the median in the elective nodal radiotherapy group hasn't been reached yet, so that might probably be around anything between four to five years. And we will see that with longer follow-up. So here we already saw a clear, clear benefit.

Zachary Klaassen: Absolutely. And then if we move to locoregional recurrence-free survival, similar results, right?

Piet Ost: Yeah.

Zachary Klaassen: We're seeing a benefit for elective nodal radiotherapy.

Piet Ost: Completely agree. And that magnitude of difference, that 20%, is almost mirrored here, which clearly reflects, and that is important when discussing next our primary endpoint, which wasn’t shown and there’s a clear reason for that. So if you treat your patient to the entire pelvis, you can tell them, "Well, in nine out of 10 cases you won't recur there," which is quite comforting. And it is 70% in the MDT, which is also not bad, but it is clearly less good. But that shows you that the majority of our patients, as we were expecting in our retrospective series, indeed are relapsing again in the pelvis. So that means that our PSMA PET, which was the majority of what our patients got, that sensitivity is not good enough. And we know that from the nodal dissection series where the sensitivity is around 40%, this is what we clearly see reflected here. Going for what you see alone probably is not good enough. There is microscopic disease in many patients that is not showing up at the first PSMA PET, but does show up at subsequent follow-up.

Zachary Klaassen: That's a great walkthrough, and I think we certainly look forward to the primary outcome, which is metastasis-free survival. I think you mentioned there's about 33 events so far, so with longer follow-up those events will accrue.

Piet Ost: Yeah.

Zachary Klaassen: So as we look at this high-level view, Piet, we have EMBARK, we have STORM data, how do we put this all together? I know this is sort of the big question as we wrap things up.

Piet Ost: Yeah, I fully agree. If you look at EMBARK, if you give your nine months of ADT for a high-risk biochemical recurrence, and do mind, the majority of the patients in our trial also had high-risk biochemical recurrence, we see that an EMBARK approach renders those patients around 17 months of time off ADT, which is quite good. If you compare that with the STORM approach, the STORM approach actually extends that period, especially when you go for the elective nodal radiotherapy, you get three years and more of your next systemic treatment at least. And probably it will be more because often these patients can get re-treated with local therapy. So that gives us probably a bigger benefit. And that gears us towards a combination therapy. In EMBARK, we didn't have novel imaging. Now with these novel imaging, we are able to see more, which means that if you combine your systemic therapy in combination with the local therapy, that is probably the winning combination.

And we are not the only ones showing that. We've also seen that in the EXTEND randomized trial, and we've seen the same in the OLIGOPELVIS Trial, which is the elective nodal radiotherapy arm as we have. It's exactly the same, but they didn’t randomize. But their outcome also shows more than that 17 months; they’re up to 26 months, which is lower than ours and probably reflects a difference in tracer. We use PSMA, they used choline. So that is also a probable difference there. But it seems to be that systemic therapy only might not be the best option. And it'll be interesting to get into a bit more detail in the publication of the RADIOSA Trial where they indeed did SBRT versus SBRT plus six months of ADT, how long does that combination render the patient disease-free? And comparing that with EMBARK and with STORM will also give us some interesting results.

Zachary Klaassen: Yeah, absolutely. I always enjoy the discussion, Piet, I feel like I learn something from you whenever we chat. I know our listeners will as well. So maybe just a couple of take-home messages for our listeners.

Piet Ost: Yep, sure. I think when you see a patient with a nodal recurrence following local treatment, there are two options you can present to that patient: that is either metastasis-directed therapy with a short course of androgen-deprivation therapy or elective nodal radiotherapy. You can clearly indicate then that the elective nodal radiotherapy will render them disease-free for a longer period. The probability of being disease-free is higher and will be longer, and the chances that they would relapse in the pelvis are also a lot lower. So that is the message we can give today.

Toxicity in both approaches is very, very low. The majority of the toxicity comes from irradiating the prostate bed if that is required, and often, unfortunately, it is, but that is the culprit of that GU toxicity. Those are the main messages that I want to give the audience and those can be immediately implemented when discussing with patients.

Zachary Klaassen: Outstanding. Piet, thanks so much again, appreciate your time discussing the STORM trial presented at ESTRO 2024.

Piet Ost: Happy to do so. Thank you for having me.