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Alicia Morgans: Hi. I'm so excited to be here with Professor Alberto Bossi, who is joining me today from Gustave Roussy where he's a radiation oncologist. Thank you so much for being here with me.

Alberto Bossi: Thank you very much. It's a pleasure.

Alicia Morgans: Wonderful. Well, I am so excited to talk to you about the PEACE-1 data, which you presented at ASCO 2023. Very exciting. We've all been waiting to hear about the radiation data, and as a radiation oncologist, this is really something I know you're very, very attuned to. So can you please remind us, tell me about PEACE-1 and how this was set up and the schematic there, and then we'll talk about what you found.

Alberto Bossi: Yeah. Correct. So PEACE-1 is a European study that has been set up by the initiative of Karim Fizazi and myself some 12 years ago. At that time, we were interested in checking in a very limited, if you want, population of patients, patient presenting a diagnosis, as we say now, de novo, with metastatic disease if one side abiraterone and, second question, radiotherapy in the prostate may change the prognosis of those patients. So these were the two basic questions we want to tackle with the PEACE-1 trial. So we set up a forearm trial. It is a little bit complex, but this was a forearm trial with a two-times-two design. So we have two arms in which the standard of care is compared to the standard of care plus abiraterone, and then two more arms in which the standard of care is compared to radiotherapy in order to have the four arms that may be studied in order to answer this question, does abiraterone and/or radiotherapy change the prognosis of these patient.

Things have been complicated as usual when you have such a time span, 12 years for the inclusion of patients, because the standard of care changes. As you're certainly aware, Alicia, the standard of care for those patients has been dramatically changing in the last five to seven years. So we had to amend our protocol because standard of care at the beginning was ADT alone, androgen suppression alone, but then we had at first to admit docetaxel, and then we put docetaxel as mandatory. So this, of course, may add in the complexity of the analysis, but give us the, I guess, unprecedented possibility to analyze a population of patient who also got docetaxel in their standard of care. And this is, I really think, something which makes our result up to date even if the study was started 12 years ago.

Alicia Morgans: I would have to agree, and I think that this study even in its earlier iterations of data has helped to drive the standard of care with the demonstration that the ADT docetaxel plus abiraterone could improve outcomes versus ADT docetaxel alone. So I think this is already paying off in the design and has kept it very, very current. I wonder, as we heard that information, we thought, "Well, the radiation data is immature." I cannot wait to hear the radiation data, and this is what you presented, so please share with us what this is.

Alberto Bossi: Indeed. Indeed. So as you said, we already published last year by Karim Fizazi the first order, the results of the abiraterone question, and indeed we need some more events for both the two co-primary endpoints. For the radiotherapy question, we were overall survival, of course, and radiographic progression-free survival because we felt that progression of the disease independently of death was an important endpoint for these group of patients. So these were the two co-primary endpoints. And indeed we had enough events just a few months ago to study and to deliver the first result of the radiotherapy arm.

And in terms of these two events of these two co-primary endpoints, we couldn't find any overall survival benefit in the population of patient presented with low-volume disease, which I remind STAMPEDE, the English study STAMPEDE, on the contrary was able to show a difference, a significant difference by radiotherapy in this setting. And this when we combine the arms in order to compare the radiotherapy arms versus the non-radiotherapy arms, but also when we made the four different groups compared to each other, so no benefit by adding radiotherapy in the low-volume population of patients. But in terms of radiographic progression-free survival, we could see that indeed radiotherapy added to abiraterone, which are very interesting synergistic effect may give some significant advantage over the other arms. So I think that when you design a study like this with such an endpoint, it's important to realize that at least one of the two endpoints is positive. So in terms of radiographic progression-free survival, adding radiotherapy to abiraterone and standard of care makes a very important difference. And this, I guess, is something important.

We also analyzed some secondary endpoints, and three of them in details, which are, of course, the toxicity of the treatment. It's always important to analyze this in a kind of study like PEACE-1, of course, but we also analyze the time to the castration-resistant state. These are in principle patients presenting with a castration-sensitive disease, and you want to see when the castration-resistant state will start in their clinical history, and we also analyze by collecting prospectively some events that we consider severe urinary events, for example, the need of a catheter, the need of a double J stent, the need of a TRP because of obstructive events in the prostate. So all these kind of events were prospectively collected because we thought probably radiotherapy may impact on those. And indeed we analyze also these endpoints, so the delay on the onset of these severe, late urinary effects.

And what is really, I think, important for our patient is that we could show that indeed for both these very important endpoints, so the time to the castration-resistant state and the time of the onset of severe urinary effect, radiotherapy make a difference, and interestingly enough, even radiotherapy alone as compared to the group without radiotherapy. So adding radiotherapy to those patients at the end of the day may delay the castration-resistant state and may delay the time to the need of this sort of local, secondary events, urinary events, and I guess also this is important for the quality of life of our patient.

And curiously enough, we found that this beneficial effect of radiotherapy is not only true for low-volume patients, so patients presented with low-volume metastatic disease, but this is also true for high-volume patients. So at the end of the day, we could show that all patients presenting with a metastatic disease of diagnosis, a diagnosis, may have a beneficial effect of radiotherapy, at least with these two secondary endpoints.

And finally, and I also think that this is very important, when we analyze the toxicity, the added toxicity of radiotherapy, we could not show that radiotherapy, at least in our schedule, which I remind is 74 gray, a very standard one, 74 gray, 37 fraction, two gray per fractions, no hyper-fractionated radiotherapy as the STAMPEDE colleagues have done. In this respect, no added toxicity by radiotherapy. And honestly, I think that this is also very good news for our patients because when you balance such an intervention for your patients, it's nice to know that you will not add any toxicity.

Alicia Morgans: Absolutely. I think this is so important and so interesting. I wonder if we can dig in a little bit to the data going all the way back to what you mentioned with the overall survival and looking at the low-volume population. You in this study did not see a difference, and that's, of course, as you said, different from STAMPEDE. So I'd love to dig in a little bit and try to understand from your perspective, why do you think we see that or don't see the difference here, but do see that with STAMPEDE? Is there something about the population? Are we just not powered? Is it confounded because of the additional therapies from the systemic perspective? What do you think it could be? I acknowledge that I'm putting you on the spot and you won't have a perfect answer, but what do you think?

Alberto Bossi: No, indeed. As you may imagine, Alicia, we have been discussing this for days with Karim in order to understand what's going on, and honestly we don't have a clear-cut answer on that. Of course, there are several, and you mentioned that several aspect of the study that may explain this difference. First of all, indeed, if you compare the overall survival in our standard of care patients, the one who didn't have any radiotherapy, and you compare this with the STAMPEDE results, well, we have something 20-month median overall survival in the standard of care arms better than STAMPEDE. So it becomes a little bit complicated to show any difference on that.

Why that? As you mentioned, probably because intensifying the systemic therapy put the bar so high that it becomes complicated to get some more survival advantage with local radiotherapy. Of course, this is just hypothesis generating. We have to dig a little bit more in our data to confirm this.

You mentioned subsequent therapy. We have been very aggressive... And this has already been showed by Karim Fizazi in the first publication of the study concerning the abiraterone question. If you look to patients that have somewhere relapsed, we were very aggressive on those one to propose a new therapy. And of course, when you look to overall survival, these may impact at the end of the day in order to better the overall survival of your population of patients. Again, we have to dig a little bit more in details in our data to show this in a statistical significant way, but this could be a second hypothesis.

You also mentioned population may not be totally comparable STAMPEDE versus our one. Yes, this may also be the case. We have used probably a much more aggressive way of staging our patients in order to rule out the nonmetastatic ones. And so these may, of course, put together a population of patient which is slightly different from the STAMPEDE one. So a lot of reason, a lot of hypothesis may explain this. I think that at the end of the day, yes, we didn't have any overall survivor benefit, but in terms of overall benefit for our patients, we are adding reasons that may convince clinicians to treat them with radiotherapy locally.

Alicia Morgans: Absolutely. And I think about the patients who I worry about with local progression and symptom development. In many cases in my clinic, these are patients with large prostates, patients who come in already at the time of diagnosis with many urinary symptoms or even obstructive symptoms at the time of diagnosis. Are these some of the patients that you think may benefit most, or is it any patient with metastatic prostate cancer that you might apply this and say, "Well, you may still benefit from radiation"?

Alberto Bossi: Yeah, that's a very good point. We will have to analyze a little bit better our data, but we have the impression with Karim that indeed patients presented with a massive local disease, patients with infiltration of the seminal vesicles already having symptomatic, obstructive symptoms due to their disease are the one that may benefit more for local radiotherapy. We have to better analyze our data, but I really think that this could be a selection criteria for those patient in the high-volume population of patients, because in the low-volume population of patient, I think that we have enough argument today to treat them with radiotherapy if you put together the STAMPEDE data and our data. We have sometimes this idea of putting result trials one against the other, but sometimes you should probably add the different result that trials may have. They shown overall survival benefit; we shown that we may postpone the castration-resistant date, we may postpone the need of local therapy. I think that for the benefit of our patient, this is both important news.

Alicia Morgans: I completely agree. I'm sure someone will be doing a meta-analysis on this soon enough to help us to put them together and really understand the outcomes more clearly, as they always do with this work. So the time to castration resistance was prolonged, which is so interesting, and you mentioned a potential synergy with abiraterone. I'd love to hear you talk more about that and what you think is happening biologically and how that may be... What's happening there?

Alberto Bossi: This is a very important point again. Honestly, we don't know because we have to admit that this is the first time that we showed on clinical data that there may be this synergistic effect of abiraterone and radiotherapy. No other trial up to now has ever had this opportunity to compare an abiraterone plus local radiotherapy arm to whatever other arms. So I really think that this is an important concept. How can you biologically explain all this? Well, it's probably a little bit too early to dig in this. There is certainly also... You know that we have been talking about the triplet therapy for this kind of patients. Well, we were discussing with Karim, and nowadays, at least for the high-risk group, where you know that docetaxel and abiraterone have now a role over androgen suppression therapy, the adding of radiotherapy may move us in the quadruplet era of the treatment. And this is also something that I leave to your comments, but it's something interesting for the next analysis of our data.

Alicia Morgans: I really think that this is something that we may discuss, and we'll have to come up with names because we keep adding and adding. We're going to be up to the quintuplet at some point, and that will be a lot. But I think that it is interesting because in the locally-advanced setting from STAMPEDE, we do know that the addition of abiraterone there in this non-metastatic but maybe locally-advanced into nodes that abiraterone was helpful in the setting of local radiation, and so there must be something there, to your point. So this is growing evidence of that synergy, which is very interesting. We'll call it the quadruplet and we'll coin the term, and someone will come along and call it something else, but it is very intriguing. I think from certain patients' perspectives, particularly those with the large prostates, that these are going to be patients who in a shared decision are going to be very keen to have this contribution to their care, especially, as you mentioned, with minimal additional toxicity or no additional toxicity necessarily.

Alberto Bossi: Yeah. With a very standard kind of radiotherapy schedule. Of course, you are well aware that in the last 10 years, more hyper-fractionated regimen have been introduced following the cheap trial and following the stereotactic body radiotherapy movement for treating prostate cancer. I'm not at all saying that today I would choose the same standard 37 fraction, one fraction per day as we have done 12 years ago. We have to acknowledge this new standard of radiotherapy. I am convinced that it'll be very difficult to show any statistical differences between all these different schedules of radiotherapy, but the good news for our patient is probably that whatever radiotherapy you do, if this is done to a sufficient dose into the prostate, may translate in some benefit for our patients. So I really think it's something that from Monday morning we should discuss with our patients during our meeting.

Alicia Morgans: And let's go there. Let's think about the clinic. Is this something that you will discuss with your patients, especially those with high-volume disease? This is where the controversy may arise as we all in the field digest this PEACE-1 data. What do you think?

Alberto Bossi: I think, Alicia, two things. Of course, you may say, and some clinicians say that, "Well, you are devoting those resource to a limited amount of patients," because we don't see so many patients presenting nowadays with metastatic disease de novo of diagnosis. But these are the patient that really risk to die from their cancer. It's not the Gleason 6, PSA 9 that will die from prostate cancer. We all know and we follow enough patients in your daily practice that these patients presented with advanced disease are the one that will die. So even small advantages that new therapies may introduce will have, in my opinion, a very big impact in terms of survival or quality of life for our patients.

So, yes, I think that we have the ethical needs, if you want, as professionals to discuss this data with our patients, to discuss data with our radiation oncology teams. Sometimes as radiation oncology, we are a bit shy in our multidisciplinary meeting to present our data and to... Well, now I think that we have some arguments also to be a little bit more aggressive in these discussions.

Alicia Morgans: Well, and I think that should always be the case, that those with the knowledge and with the tools to help our patients should never feel that they're not empowered to speak up. So I am excited to continue collaborations with our radiation oncology team members. You certainly add a lot to our patients' outcomes, and certainly this is what we wish, to do the best that we can for them. So as you finish this up and think this through, what would your final message be to the listeners about the PEACE-1 radiation data?

Alberto Bossi: So I will say number one, yes, we could show that radiotherapy on top of standard of care may add some benefit to patients independent of the burden of the disease at diagnosis, and this especially in terms of quality of life because prolonging the castration-sensitive, so prolonging the onset of the castration-resistant state in terms of quality of life is important, and also preventing local symptoms is also important in terms of quality of life. This is something that may make us think to an intensification of your treatment. I am well aware, and you mentioned that probably we also have to think about de-intensification treatment. We didn't show this with PEACE-1, but the message is probably that not all patient may need a full month of treatment that we have studies in PEACE-1. We have to be very, very honest and realize that the next years may tells us, for example, from the biology of the disease, that some patients will be well served with less intensive treatment. This is also something the community should be aware of.

Alicia Morgans: Absolutely. And over time, we're going to be able to really meet the patient where he is in terms of the right intensification strategy or de-intensification. I so appreciate that you and the team are helping us find our way and understand things more clearly. Thank you so much for your time and your expertise.

Alberto Bossi: It was a pleasure. Thank you to you, Alicia.