Piet Ost: Thank you.
Daniel Spratt: Thank you so much.
Piet Ost: So thank you to have the opportunity to recreate our debate. So the claim was that early salvage radiotherapy is equivalent to adjuvant radiotherapy. These were my disclosures for the talk. And I actually, as every speaker does, wanted to change the title, of course. And I wanted to consider that adjuvant radiotherapy should be superior to early salvage for us to consider that. And I will give you some of my opinions on why that should be the case. And I also do think that if we think about escalation or de-escalation treatment, I do think that the deescalation trials do not always need to be non-inferior. So if we impose someone or think we have to treat more patients, then maybe treating in a more intense way or treating all patients should be the one that has by far be superior. And this is one of the interesting papers on that.
So what is the cost of a universal adjuvant policy if we consider patients with high risk? Well, we would need to irradiate rather a hundred patients for only 30 of them to actually benefit. And of course, if you look at high risk, we all know that's a spectrum. So this is considering, for example, having one high-risk factor. And that would be an overtreatment of so many patients that ultimately won't benefit. And we should also consider, of course, that we have a very sensitive tracer, a good biomarker being PSA, which is now ultrasensitive, measuring probably too many numbers behind the coma for our patients. But nevertheless, it allows us to track the disease if the patient allows them to be followed in that correct way.
We have three randomized trials. They all asked the same question and they all came up with the same answer. So here you see an overview of the RADICALS, the RAVES, and the GETUG, with RADICALS, of course, being the largest one. And none of them actually saw a benefit of giving immediate adjuvant over early salvage. And I think this is the biggest evidence we can have, which is later also reflected in the guidelines, and I will come back to that. And if you pool all of these trials in a meta-analysis that was published a couple of years ago, you do see that an immediate adjuvant treatment doesn't really have a benefit over early salvage and there's no benefit in terms of event-free survival or whatever endpoint you actually want to pick.
The other point we want to consider, if we think of adjuvant treatments, we have to think about side effects. And if an adjuvant treatment wouldn't have any side effects, of course that will be fine. You can treat your patients, but everyone has seen these side effects like diarrhea, proctitis, cystitis, haematuria. They're real. And the more patients you expose to it, the more patients that potentially will have these side effects. Do mind that many of these trials are a bit older and modern techniques might reduce them, but you will expose more patients if you treat more. And here's some of the other ones, like urinary incontinence or faecal incontinence, which also might be higher if we treat all patients.
So what if you combine and have a bit of a higher risk profile? Yes, you might see a tilt more towards that adjuvant might be getting closer. So you would, for example, if you take several high-risk factors together, if you eradiate 100 patients, probably 80 would benefit, but still you're over-treating. And there's some beautiful examples in literature of surgical trials where indeed if you look at these curves, especially the blue one where surgery alone gives you an event, so that means that the treatment has already failed within two years of approximately 50% of these patients, which is something important to consider. So if you have more high-risk factors, you need to treat or you're over-treating less patients. But nevertheless, who are these ideal cases? And that's something we still don't know. Here, for example, even in node-positive patients, not a big difference. Here we see that the potential might be bigger if you have more positive lymph nodes.
What is important and what early salvage therapy doesn't cover is waiting too long. Waiting too long is a bad idea. Positive nodes typically not represented in the trials waiting for a PSMA PET to become positive or having persistent PSA. That is not what we believe early salvage should be. And the prerequisite, of course, that you should be able to do adequate PSA monitoring. If you are in a situation where that is not possible, discussing adjuvant radiotherapy might still be a good idea if there's no good alternative. But the guidelines do agree that the condition has been met, both EAU, NCCN, ESMO, they all point in the same direction. And of course, Dan is part of NCCN, so he must support that salvage radiotherapy for sure is a good option. He has no other way to agree, at least on that point.
So in summary for me, there are three trials, one meta analysis, they all see the same. You can discuss about the word equivalent, but let's say adjuvant at least isn't superior in all of these cases. So with that, I'm happy to and to discuss more in depth.
Leslie Ballas: Thank you, Professor Ost. Dr. Spratt, are you able to give us the other side of the debate?
Daniel Spratt: Happy to. Thank you so much for having me. And my task was to really take the counterpoint and really this is for educational purposes to see both sides. So these are my disclosures. And so I think what's important for people is to just to make sure we understand the terminology that we're talking about here. And so many of us are familiar with what we call non-inferiority trials. And so you usually will set a non-inferiority margin, and that margin you have to stay within. And so for example, in this hypothetical example, you would say that depending what your control arm is, adjuvant would be superior, it doesn't cross one, or you would say early salvage radiation is inferior. But for example, in this case here, you would say adjuvant is non-inferior because it doesn't cross this non-inferiority margin, or if your control arm was early salvage, then it does cross this non-inferiority.
So you would say early salvage is not non-inferior. But something that I think we rarely do in oncology because the trials need to be massive, many thousands and thousands of patients, is to do what we call equivalence trials. And this is where you need to now meet both bounds, where you need to make sure it's not better or worse. It really is tight where that effect size estimate is around one. And so this would be an equivalence trial that you would see the result versus something like this, you would say it's not equivalent. So as Piet already discussed, there's been three Phase 3 randomized trials done around the world. And I think that, while all of them are very important and I credit to all the trial groups and patients, is the RADICALS trial is clearly, as you can see, the largest, larger than the other two combined and the only one that actually completed its accrual. So focusing more on the RADICALS trial.
And I think what's also important to note is to get on this trial, they were also enrolling multiple other randomized trials through the RADICALS consortium that were testing different hormonal questions. And as you see here, patients that they felt needed adjuvant or those that absolutely did not, they would not go on this trial. It was really patients they had uncertain feelings about, and that's really who went on this. So as you'll see by the demographics, a lot of the more aggressive patients were not enrolled on this trial. And when you compare the patients that were on the Landmark ProtecT trial, which is again, a trial where we don't really show much benefit to treatment versus active monitoring, so a fairly lower risk population, you can see here that definitely the RADICALS trial is a little bit higher risk, but it's not a true high-risk trial like the trial Piet showed, the CALGB trial, which you can see is a true, we'll call it high-risk trial.
So it's a relatively favorable population that was enrolled in RADICALS and the debate here is about high risk and no positivity. And so the primary endpoint of that trial, despite the favorable population, when they did their, I wouldn't call long-term follow-up, about seven years or so follow-up, you can see the hazard ratio was actually significantly better for disease-specific survival with adjuvant radiation. This was actually the original primary endpoint of this trial, and they changed it because they were concerned there may not be enough events and so the changes will get to freedom from metastasis. But again, if you plot what this looks like, you're going to say here, because the control arm was early salvage, you would say early salvage is inferior technically for disease-specific survival. It's not non-inferior, and it's definitely not equivalent. When you look at their new primary endpoint that they changed, again, the hazard ratio strongly trends, but not statistically significant right now, for favoring adjuvant radiation.
So again, this here it does cross one, but you would definitely not say... You couldn't even say it's not non-inferior and it's definitely not equivalent. It is favoring adjuvant radiation in this more favorable population. But what a fair counterpoint for patients with, let's say, intermediate risk disease is that the absolute benefits in these endpoints was small, 2% benefit at 10 years of adjuvant, maybe 3% difference at 10 years for distant mets here. But remember that this population again is pretty favorable. If you look at distant mets rates or death from prostate cancer rates in an actual high-risk population, they're markedly higher. And so when you apply those rates to, let's just say, disease specific survival and you apply that hazard ratio, if your baseline risk with salvage is 20%, that hazard ratio, you may now reduce that to 7%. So that's almost a 13% absolute benefit. And people may say, "Well, Dan, you're jumping through a lot of hoops here to get to this."
Well, the reality is we just don't have the data to say in high-risk disease, what is the benefit? So I think for me for intermediate risk, totally fine if adjuvant goes. I think those absolute benefits are small, but only if early salvage is used, which in the United States, a lot of men, over half, do not get referred for early salvage. As Piet already said, we should not be waiting for imaging positive disease as a standard of care. And in high-risk patients, most are going to need radiation. And so I think that you're not going to over-treat nearly as many patients. And there's a real possibility that adjuvant might be better. We don't know for certain, but ideally, if possible, you do wait a few months for patient continence to improve because quality of life does matter. So with that, thank you so much.
Leslie Ballas: Thank you to both Piet and Dan for going over the debate. I think that both of you had compelling arguments. And so just to help me figure out what to do, when you're talking about high risk, Dan, are you just including Gleason 8, 9, 10, which was the underrepresented population in the adjuvant early salvage population? Since I don't think any of the early salvage trials included node positive patients.
Daniel Spratt: There's a small percent that did have node positivity. It's small.
Leslie Ballas: Oh yeah. I guess.
Daniel Spratt: But I think if you have a patient with Gleason 8 to 10, we'll say T3B, especially because T3A is not a very prognostic. I mean, in the ProtecT trial, a lot of patients had T3A disease. So T3B and no positivity, especially multiple of those factors. I think when we start talking about a patient that in the RADICALS trial, about half or less ever recurred. So yeah, you're going to over-treat quite a bit of guys to just jump in and give adjuvant. But if you're talking about a population that's 90% will just say are going to recur, to me, it's an open question that I don't know how we'll answer if anyone's really that interested in running that trial, but it's uncertain to me that I can confidently say, especially with the way practice is done, where I still see patients at PSAs of 0.5 on a monthly basis, I don't know. Adjuvant at a population level might be better, but that also could be I'm not seeing them at a PSA of 0.05, 0.07, 0.1 and pulling the trigger.
Leslie Ballas: One thing that both of you agreed on and I want to touch on is that postoperative radiation should not wait for imaging positivity. And I think that's a really important point that a lot of patients and even providers get lost in given the new technology of PSMA. And so maybe each of you could speak to why that should not be the practice. Piet, do you want to start with that?
Piet Ost: Sure. And the misconception might be that if we look at all the, I would call it marketing that has been done around PSMA PET, it seems like a tool that picks up all the disease all the time and doesn't have any drawbacks like false positivities. The truth, of course, is that it does and that is very unfortunate that at these lower PSA levels, often it doesn't pick up anything. And that's the one problem, although the disease is there because the PSA is rising, you know that there's something, but the sensitivity is not good enough. And there's very nice data that if you treat the disease locally, that is typically where in the region of the prostate bed, you do have a benefit. PSA drops despite the negativity of that PSMA PET. So that already shows you that that sensitivity is too low. Waiting for the PET to become positive, often you are facing PSAs above 0.5 and there will be some prospective data coming that indeed the previous studies, the retrospective series were way too optimistic.
And if you have to wait about 0.5, then you're not only talking about postoperative radiotherapy, but then the hormones come into play as well. So you're making the disease become worse. Maybe we even have to adapt our field where we have to add a pelvic field, we have to add the hormones. So all of a sudden we are facing something different, and you might also risk a higher likelihood of having distant disease because the higher the PSA goes, the higher the likelihood that the prostate bed only won't cut it here. So these are all things we need to consider. There's only one good chance to cure your patient and that for now with the evidence we have today is as early as possible.
Leslie Ballas: Dan, do you have anything to add to that?
Daniel Spratt: Yeah, I completely agree with Piet. PSMA PET or any imaging, MRI people believe is far more sensitive than it is. And I think to keep it basic, we can't detect the threshold of a PET technology, you can't see something less than, you could debate less than like three millimeters, the actual positrons, it technically cannot. And so on millimeter is still a lot of cancer cells, let alone true microscopic disease. And I think the big misconception is that when people say, "Okay, we waited, we now see," let's pretend, "a lymph node." Do you really think that's the only disease? It still has all the microscopic disease you can't see. And I think Piet's run an amazing to STOMP trial. There's been numerous trials out. And once a patient even has multiple oligometastatic disease in the pelvis, let alone metastases, we control the vast minority if these patients are truly disease free at 10 years.
When we look at our early salvage radiation series, we control the vast, vast, vast majority of these patients. And again, I realize these are not apples to apples, but it's pretty clear from multiple studies that the higher the PSA goes, the higher the likelihood you will find metastatic disease. And we have to be real. Cancer needs a niche. It needs an environment. You just took out the prostate, it doesn't have a great home. The longer you wait, it wants to find a good home, a good blood supply. So to me, this is a trial question, and I encourage the trial to be done. I could be completely wrong with what I think, but to me it's absolutely not the standard of care to just wait and often again, you're waiting for patient to metastasize.
Leslie Ballas: Great. All right. Well, listen, thank you both for being here and for sharing your expertise. We all at UroToday benefited, and so thank you again.
Daniel Spratt: Well, and it's very important, Leslie, Piet won the debate. It was like, I forgot the poll, but it is the vast majority of people in this setting would recommend early salvage radiation. So important to know.
Leslie Ballas: Congratulations Piet!
Piet Ost: Caveat there, we did vote prior to the debate. There was no revoting after the debate, so we can't 100% know here, but true. Before the debate, I won.
Leslie Ballas: Fair enough. Thanks again.
Daniel Spratt: Thank you.
Piet Ost: All right. Thank you guys. Bye-bye.