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Alicia Morgans: Hi, I am so excited to be here today with Professor Thomas Zilli, who's a radiation oncologist joining me from Lugano, Switzerland. Thank you so much for being here with me today.

Thomas Zilli: Thank you so much for your kind invitation. It's my great pleasure to be here today.

Alicia Morgans: Wonderful. So I wanted to speak with you about a very important study, PEACE V, which you presented at EAU 2024. I'm really excited to hear the updated safety data and information from this study. Thank you. And, please, tell us what was the reason for the study and the study design.

Thomas Zilli: Yeah. So when we started to conceive the study in 2018, we had two different strategies to treat patients with oligorecurrent and other prostate cancers. We had the first data coming from the STOMP and the ORIOLE trials, so treating just with focalized SBRT to lesions, and we had more comprehensive irradiation, including also the prophylactic regions inside the treatment pelvic region. And the question was, which is the winner in this case and which is the best strategy that we can use for treating these patients with oligorecurrent prostate cancer?

And with Piet Ost, we started to conceive this trial, the PEACE V, so-called STORM trial, randomizing patients with nodal oligorecurrent prostate cancer, confined to the pelvic regions. And we decided to randomize these patients in MDT strategies. So, in this case, it's using SBRT, 30 Gy in three fractions. So like STOMP, for example, or we considered also using MDT, including patients treated with salvage lymph node dissection.

And this was their arm A, both strategies combined with six months of ADT. The other arm consisted of randomizing patients to receive the same strategies. So salvage lymph node dissection, followed by elective prophylactic nodal regions irradiations, or an elective nodal irradiation, treating the involved nodes, using an SIB boost, both combined with ADT. And so, the goal was in this phase 2 randomized clinical trial, with a superiority design, to prove that elective nodal irradiation can improve the outcome of our patients. And the primary endpoint was metastasis-free survival.

A secondary endpoint was also biochemical progression-free survival, local regional relapse toxicity as assessed by CTCAE Version 4.0. And we had also the quality of life using the EORTC questionnaires. All the patients were restaged after the first biochemical failure. So there were patients treated on the primary, with radiotherapy or radical prostatectomy, already receiving or not the prostate bed irradiation, but not the pelvic nodal irradiation. And these patients were randomized after realization of PSMA PETs or even choline PET. So just to consider that we had almost 80% of the patients staged using PSMA PET and just 20% using choline.

Alicia Morgans: And that sounds like it's actually very consistent with the way that the field has gone in terms of imaging strategy, with most patients getting these PSMA PETs, so this makes sense. So what did you find?

Thomas Zilli: So, at the EAU, we presented the 24-month toxicity. Since we already published the acute toxicity, we were able to show that elective irradiation was no more toxic compared to a focal strategy. So we need just to consider that only a minority of the patients received a salvage lymph node dissection because the majority of the patients were just treated with radiotherapy. And when we presented the data consisting of the 24-months toxicity, we observed that the worst 24-month Grade 2 or more GU toxicity was not significantly different between the MDT, the focal SBRT versus elective nodal radiotherapy.

We had around 20-25% of Grade 2 or more exceeding the baseline GU toxicity. Considering the GI, so the rectal toxicity, we had very few events. During the first 24 months, we had less than 6% of Grade 2 or more toxicity. So we were finally able to demonstrate, and this, I think, is really important because we will see the results in terms of outcomes that will be presented during the next ESTRO meeting.

And with this 24 months of toxicity, we were able to demonstrate that, finally, even when we are treating with a prophylactic intent of the pelvic region, we don't increase the toxicity of our patients. So this, in terms of safety, could be a valid treatment option. Recently, we have the data from the OLIGOPELVIS GETUG trial presented, showing quite interesting results in terms of biochemical disease control for patients, again, with oligorecurrent prostate cancer, but staged in this case mostly with choline.

So having a higher PSA. So I think it's proof of concept of a different treatment strategy in which we include also the prophylactic in other regions. So we all know the limitation of PSMA imaging in detecting macroscopic disease, and this could be a valid treatment option in terms of safety. We'll see in a few weeks the results in terms of biochemical relapse-free survival, and also local regional control between the two different strategies.

Alicia Morgans: I agree, that will be so interesting to see, but really quite reassuring that the toxicity, at least, is very similar. Now, I want to ask before we move on about some limitations. And one question I have, it's not a limitation, but how did you choose the six months of ADT? And the reason I ask is that the RADICALS study suggests that particularly for patients with high-risk features, it might be beneficial for them to have a longer course of ADT, maybe 24 months. And obviously, this study was designed before we had access to that data. So I'm just curious what your thoughts are there.

Thomas Zilli: Yeah, this is a good question. So I think that in this setting, unfortunately, we don't have any clear indication on the duration of ADT. So, at this time, the question was even if we need to add the ADT in these cases, because mostly based on the STOMP, ORIOLE trial, there were many centers treating these patients just with SBRT alone. And finally, we had the first retrospective data suggesting that when we add the six months of ADT, we can improve PFS.

Now, retrospectively, of course, the question remains open if we needed to have a longer ADT, like RADICALS, for example, 24 months. Or, on the other hand, if we needed to intensify the treatments using RP. We have data now coming from the EMBARK trial, suggesting that when we associate ADT and enzalutamide, we can improve MFS for patients having high-risk biochemical failures. And finally, the majority of these patients were in this category because we had quite a rapid PSA doubling time. We had a median of six months. We had a PSA of one at relapse. So it means that probably these patients were eligible for an EMBARK, so they had the EMBARK criteria to be treated with enzalutamide and ADT.

Now, the question remains if these patients that are treated with intensified regimens could be intensified even using this treatment approach, using radiotherapy. And this is an open question. Of course, we decided just to use six months. OLIGOPELVIS has done the same thing. We know that we have ongoing trials looking at the impact of six months of affinity.

We have the ADOPT trial, for example, in the Netherlands, which randomized patients between SBRT or SBRT plus six months of ADT. This was the decision at the time, but I think the times are rapidly changing. And probably to design new trials, we need to think about RP, for example, or other treatment stratification. Then the concept for the duration, I think, remains really an open question.

Alicia Morgans: Yes. And it's certainly not a criticism of the trial, certainly as you said, designed in 2018. And I would also say that EMBARK included patients who had maximally treated pelvises. So really, they had recurrence in this high-risk disease after this time point where STORM fits in. So I don't think that you did the wrong thing, even knowing that EMBARK came out much later than this particular study, because that is a population that's already had the pelvic radiation that you're delivering in this trial. Either way, really interesting questions. And I also look forward to seeing the quality of life data that I think was collected and hopefully will be presented at some point in a near-future meeting as well. So I wonder, as we think about all of this, what is your message to listeners, what should we think about this, the safety data, suggesting, hopefully, no increased safety signal. And what should we look forward to in terms of future data to come out of the STORM or PEACE V trial? Very exciting.

Thomas Zilli: Yeah, so I think the take-home message is that treating the prophylactic in other regions, using a 45 Gy schedule, doesn’t increase the toxicity compared to a focal SBRT. And this is an important message because sometimes we are afraid to use elective radiation because we had the idea it would increase the toxicity in this case, but this is not true based on our data. Of course, now we need to validate this strategy. Because, at the beginning, this was a superiority trial, with the idea that elective nodal irradiation can improve the outcome of these patients having an oligorecurrent disease.

I think that we need to wait a few weeks to have the first answer, not for the primary point, but at least for the biochemical relapse-free survival and the local regional relapse. Because we know that treating with focal SBRT we can repeat SBRT again, but we have sometimes just local relapses inside the pelvic region. And probably with elective nodal irradiation, we can prevent the next relapse. The question remains if this strategy can prevent relapse in the paraaortic regions and have an impact in terms of metastasis-free survival. For that endpoint, this primary point, we need to have more events. At this time, we don’t yet have them.

Alicia Morgans: Wonderful. Well, thank you so much for reporting this. I think the oligorecurrent state is absolutely one in flux right now in prostate cancer, one that we're keeping our eye on, trying to understand the implications around whole-pelvis SBRT radiation strategies, as well as our systemic therapy options. And really, the STORM or PEACE V trial gets us a step closer to understanding, at least, the radiation perspective. So thank you so much for your time and expertise, and we look forward to more data coming out of this study. Thank you.

Thomas Zilli: Thank you.