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Alicia Morgans: Hi, I'm so excited to be here today with Professor Alberto Bossi, who is joining me as a radiation oncologist who practices in Paris, France. Thank you so much for being here today.

Alberto Bossi: Thank you for the opportunity.

Alicia Morgans: Wonderful. So you gave a beautiful state-of-the-art lecture at EAU 2024, and really helped us integrate an understanding of how we think about treating the local prostate in the setting of metastatic hormone-sensitive prostate cancer, predominantly thinking about PEACE-1, but also all of the studies that have helped to understand this. And I'd love to hear your thoughts on this topic. Thank you so much for sharing.

Alberto Bossi: Thank you. Thank you, Alicia. Well, indeed, it's an important topic because, as I said in my lecture, we may see few patients having upfront metastatic disease. But still, these are patients for whom if we are able to offer treatment that may impact overall survival, well, this would be a very important step forward in this field. So I really think this is an important space in which we are all involved. So I was asked to try to identify the subset of patients that may most benefit from local treatment radiotherapy in this setting. And this is not an easy task because even if the major guidelines all over the world, EAU guidelines here in Europe, but also American guidelines, all state that local treatment, especially in the low volume population of patients, is required, well, we don't have any other suggestion on how to better identify those patients.

And you are well aware that there are randomized trials that have been done, especially in Europe on this subject. The STAMPEDE group has done one, the HORRAD Netherlands group has done another one in which radiotherapy, and this was true in a meta-analysis of those trials, was able to impact overall survival, especially in the low volume population of patients. But this is the first question to discuss probably, how to define in 2024 this low volume population of patients? Because we all know that this was done with very standard exams like bone scan, CT scan, which are not at all what we are using today. Today, most of those high-risk patients will get PSMA new generation imaging. Do the results that we have accumulated up until now in this field also apply for patients having PSMA staging? We don't know. So this is a very big first point that I think clinicians should be aware of.

And indeed, if you use a bone scan as the main exam for staging of those patients, we have solid data out there with even a cutoff that has been fixed that we all use in clinics; bone scan should be the cutoff to identify patients that may benefit from local treatment. And this, of course, is something very easy to use in daily practice. And this PEACE-1 was a little bit adding confusion to this landscape. We realized that probably overall survival is not the only endpoint that patients are interested in, especially those kind of patients, they are well aware of having a disease, which is a very high-risk disease. So I don't think that overall survival should be the unique endpoint at which we must be interested. And indeed, my further conclusion was that if you look at PEACE-1 data, there are at least two other major endpoints that should be discussed with patients, which are the likelihood of postponing local symptomatic development of the disease and secondly, the possibility to postpone the castration-resistant phase of the disease.

I don't know what your opinion is, Alicia, but I think that these may be very important endpoints too. So I'm really convinced that the possibility of using local radiotherapy to postpone the severe local effects of the disease and also to postpone the castration-resistant phase of the disease are important endpoints. Our patients are not only asking for quantity of life, but they are also asking for quality of life. And my conclusion here is that we, as professionals, should integrate the patient in the discussion and not only think about what we think are the real endpoints that are important for them, but ask them, "What's your endpoint?" And if this is the case, the burden of the disease, low or high, I think it's of secondary impact on our choice. What counts here is really how the patients see their disease and what they are expecting in their future. And this, I think, is probably the most important message of the PEACE-1 trial and in general on how to better identify patients that may benefit from these treatments.

Alicia Morgans: So I think these are such great points. And let's start with some of your latter points, really thinking about these endpoints of importance that are different than overall survival because as you said, there are things that matter to patients. Certainly, there are also things that matter to clinicians that are in between current disease control and overall survival, which is a very distant endpoint when we're talking about metastatic hormone-sensitive disease and all of the things that come before someone passes, we hope. So things like time to castration resistance and certainly preventing complications, urologic complications, things like needing catheters or percutaneous nephrostomies, other stent procedures, they seem very important to patients. And from your perspective, what is the burden on the patient to receiving this local radiation to the prostate versus the potential burden that they may have from those types of procedures? Is this a fair trade, or is this a relatively low burden procedure, this radiation to the prostate, that may prevent something that's actually much more troublesome?

Alberto Bossi: Yeah, that is a very good point. So first of all, I also had a slide in my presentation in which I really wanted to check how, for example, a resection of the prostate may represent a burden for a patient. Because when I presented those data to some urology community here in France or in Europe, well, urologists, they always said, "Yeah, but preventing a resection of the prostate is not such a trivial endpoint because resection of the prostate is not necessarily a very troublesome procedure." But when you look at the EAU guidelines in which resection of the prostate is highlighted and analyzed, well, you realize that there is some possible toxicity linked to this procedure. So the idea of postponing it with local radiotherapy may be an interesting one for our patients.

And on the other hand, we have to also remind Alicia, that local radiotherapy has been shown, at least in our hands in PEACE-1, but also in the STAMPEDE hands, not to add any severe toxicity per se. The data we have shown that the local radiotherapy does not translate into any specific toxicity for patients. So the real trade-off here, I guess, is really important to discuss with the patient and their families too.

Alicia Morgans: And part of this trade-off, outside of the toxicity of local treatment, may be urinary frequency or symptoms and some bowel symptoms, is the time commitment. And I think it was really interesting in STAMPEDE that this was a once-a-week delivery of radiation. How did you deliver it in PEACE-1? And as you think about implementing this in practice, what approaches could be taken to limit the burden of time even for patients who want to have local treatment for their prostate?

Alberto Bossi: Yeah. So in PEACE-1, we had a very standard radiotherapy because you can figure out that when we designed the trial more than 10 years ago, well, hypofractionated regimens were not so popular, especially in Europe, in France especially. So we had to go for something very standard, 37 fractions in seven weeks. But of course, if PEACE-1 had been designed yesterday, we would certainly go for a more hypofractionated regimen. We know now that this is totally effective, so no problem in implementing a more hypofractionated regimen, which also translates into a more patient-friendly treatment. So no doubt about that. If I may, I would also like to discuss for a few seconds the impact of radiotherapy on another endpoint, which is radiographic progression-free survival, which is sometimes a little bit misunderstood.

But if you put yourself in the perspective of a patient, the idea of reporting a progression of the disease in the bones, because this is what radiographic progression-free survival means, is also not trivial. And we found that local radiotherapy may also prevent the progression of the disease in these terms. So this is another point that I think should be discussed with patients in detail when proposing local radiotherapy.

Alicia Morgans: I completely agree. I think that as we consider from a patient's perspective, the impact of having changes on their scans is actually quite impactful, very stressful, anxiety-provoking, and also may come with symptoms of fatigue, pain, and other burdens that are very meaningful to patients. So I appreciate you bringing that up. One other thing that you also mentioned though that I want to make sure we touch on before we close is the changing imaging landscape that is something that is absolutely affecting our understanding of high versus low volume. And in PEACE-1, of course, you found that the benefits that we've talked about outside of overall survival actually seem to span across the spectrum of volume, which is important to make sure we reiterate. But as PSMA PET is coming into the fore, I find myself having some challenges in understanding if a person is high or low volume, and I'm going back and not just reading the report, I'm looking at the images and trying to understand if there is sclerosis on that CAT scan? Is it truly high volume, low volume? It can be very challenging.

And so how do you think about this as you are trying to implement and even moving patients with stage migration from a localized setting maybe into a low volume by PET? How do you think about this as you try to implement this in your practice?

Alberto Bossi: Yeah. This, I guess, is one of the challenges that we will have to face in the next few months, not years, even months, because this will be something which our patients will bring with them PSMA in every consultation. So I really think, in a very straightforward way, that the idea that radiotherapy locally may benefit patients independent of the burden of the disease will make us a little bit more confident to propose radiotherapy also in high-risk and high-volume diseases, not only in low-volume diseases. Of course, we will see more and more patients with low volume disease due to PSMA, but for those, we even know that overall survival benefit is present when doing radiotherapy. So I guess this will not move too much our treatment indications for these patients.

Alicia Morgans: Yeah, actually it's such a great point that especially because the benefits seemed to span across the spectrum.

Alberto Bossi: Correct.

Alicia Morgans: Perhaps this is less of an issue, but I still struggle sometimes with those patients with locally advanced and now more metastatic disease on PET. Although in those patients, I'm still treating the local prostate and then using intensified hormonal therapy. It truly is such a moving target, and I sincerely appreciate your time as you talk us through. What is your final message to listeners, your summary of the talk as you let them go out into their practices and think about radiation to the prostate in this setting?

Alberto Bossi: I really think, Alicia, that from Monday morning, as we used to say here in Europe, it will be very important to put the patient at the center of our discussion, to involve them, to understand that overall survival may not be the only endpoint they are interested in, and to discuss with them the benefits that local treatment may imply for the rest of their life. Perhaps not giving more time, but probably certainly giving a better quality of life. And I think that especially for this subset of patients, putting them at the center of our perspective is the most important message.

Alicia Morgans: Well, thank you so much. I think that's always the message that we have at UroToday and certainly in my practice. And I appreciate your time and your expertise in ensuring that we put the patient at the center of all these decisions. Thank you for your time.

Alberto Bossi: Thank you, Alicia.