Managing PSA Recurrence After Prostate Cancer Surgery Treatment "Discussion"
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Silke Gillessen, Aurelius Omlin, and a panel of experts engage in a comprehensive discussion about managing biochemical recurrence in prostate cancer patients. They cover key scenarios including PSA persistence after radical prostatectomy, timing of salvage radiotherapy, and the role of PSMA PET imaging.
Biographies:
Silke Gillessen, MD, Medical Oncologist, Medical and Scientific Director, L'Istituto Oncologico della Svizzera Italiana (IOSI), Bellinzona, Switzerland
Aurelius Omlin, MD, Medical Oncologist, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
Biographies:
Silke Gillessen, MD, Medical Oncologist, Medical and Scientific Director, L'Istituto Oncologico della Svizzera Italiana (IOSI), Bellinzona, Switzerland
Aurelius Omlin, MD, Medical Oncologist, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
Read the Full Video Transcript
Silke Gillessen: These were three questions. So what do you recommend for a patient with PSA persistence, and we defined it as more than 0.1 post-radical prostatectomy pN0 on extended PLND again and a negative postoperative PSMA PET provided the patient has regained continence?
And we ask that for three different scenarios. So the PSA is 0.2, and the patient didn't have any risk factors. So you see here it's about half-half of the panelists said, OK, let's monitor this patient and salvage therapy in case of further PSA rise. And 44% were for immediate therapy.
If you look at the scenario with the PSA much higher, 0.7, but again, no risk factors, you see there's a big change. So monitoring is only in 18% of the panelists would go for monitoring. And if you have no PSA defined, but two or more risk factors, it's even less of the panelists who would go for monitoring. So there, I ask you first to comment please on these results.
Derya Tilki: Yeah, interesting results. And it's really the point which is important, is that there are no risk factors because we cannot only look at the PSA but also at the risk factors. And there have been studies looking at the percentage of PSA value at persistence compared to the preoperative PSA.
And a patient, for example, with 0.2, could have had quite a higher PSA before surgery. And it could be at four weeks. So that would be a candidate for monitoring, like a lot of panel members voted. But at 0.7, it's quite clear that there is disease, and therefore the majority opted for immediate therapy, which I would also opt for.
Silke Gillessen: Thanks. Barbara, do you want to say something from the radiotherapy side, how you are managing these patients?
Barbara Jereczek-Fossa: Yeah, very interesting results. What I think is missing here to make a decision is maybe the doubling time. Because we have one value of PSA. And I think that it also would be good to know the next one, so then you can—it's easier to make a decision.
And definitely, patients, all of them are already, let's say, detectable PSA. So yes, we discuss salvage radiotherapy. I think I voted too.
Silke Gillessen: OK, perfect. If there are no questions—I don't see very well—then we go to the next.
Aurelius Omlin: So now we move on to the topic of biochemical recurrence after radical prostatectomy for the majority of patients. Something you will see very frequently at your MDT. Now, patients, we use this EAU high-risk criteria, PSA doubling time of less than a year, or ISUP grade four or five cancer.
And what do the experts recommend in case that there are no additional risk factors for local relapse as defined on the slide? Option one is salvage RT plus/minus systemic therapy—we didn't want to make it too complicated—as early as possible, as you heard today. Even before 0.2 PSA. Or wait until PSA is 0.2. That's option two. And do a PSMA PET if this informs your decision-making, or systemic therapy alone.
And you see here, 41% voted for as early radiation as possible. 57% voted for waiting until PSA is a bit higher and do a PSMA PET. And if there are additional risk factors, the picture changes a little bit. And now 63% would go for as early as possible radiation therapy. 37% would still wait until PSA 0.2 and do a PET.
Now, let's discuss this. We have a lot of radiation oncologists here on the panel. Maybe Thomas, what's your strategy in these patients?
Thomas Zilli: I think, of course, it depends on the PSA. But having a PSA doubling time less than one year, so we have a patient with a high risk. Of course, doing a PSMA PET-CT, we can detect where is eventually the disease.
But of course, we have just 40%, 50% of the patients having PSMA-positive lesions. So I think nevertheless, we have quite strong evidence to recommend early salvage radiotherapy in this setting. So I think that we can change the treatment management, and that finally, the indication to treat with salvage radiotherapy remains.
So personally, I voted for one, in this case independently of the presence or not of risk factors, but this is my opinion, of course. I don't know the other colleagues.
Aurelius Omlin: Is the PET even necessary? I don't know whether someone from nuclear medicine wants to comment. At a PSA approaching 0.2, does it make sense—do we waste resources if we go for a PSMA PET knowing that the chances of finding something is small?
Barbara Jereczek-Fossa: It's really—at least in Italy, it's not so easily available. So waiting list is one or two months for PET. So PSA would be already higher. So we don't ask for PET with this PSA level.
Jason Efstathiou: We have institutional data that suggests even in PSAs less than 0.2, there's up to a 50% finding on a PSMA PET. It's surprisingly higher than one might think. Some of the literature would suggest 30%. So I would—
Aurelius Omlin: A true positive finding, or?
Jason Efstathiou: Well, I mean, not necessarily biopsy confirmed, but not just kind of random little rib things either. But I guess I would say, and I'd love to hear from the other radiation oncologists on the panel, the data is supporting early salvage.
And early means the lower the PSA, the better. And I think we saw it throughout this morning's talks, that level might be even under 0.2, right? So I'm sort of surprised by these results, especially even the second one. Why isn't it closer to 100%? Why is it only 63%? It is the only potentially curative treatment still on the table. I don't know, any comments?
Paul Nguyen: Yeah, I would agree with you, Jason and Thomas and others, that we should start salvage radiation as early as possible. I do worry about the way option two is worded. That it could be misinterpreted about performing PSMA PET. That if the PSMA PET is negative, that we would then continue to wait until the PSMA PET turns positive before doing salvage radiation. So I think that's just important to clarify in the manuscript. I don't think we should be waiting for PSA PETs to turn positive before doing salvage radiation.
Ray McDermott: My concern there is you're denying people potentially curative treatment waiting on a result that will only affect 50% of them potentially. So I think it's a mistake. And I think you should just go ahead.
Derya Tilki: Yes. So I'm not a radiation oncologist, but I also have a comment. So in the EAU guidelines, PSMA PET-CT is recommended, but it shouldn't delay treatment, that's for sure. And I agree with Jason that a lot of these patients with high-risk EAU BCR do have a positive PSMA PET even below a PSA of 0.2.
And the sense of doing it is not to avoid radiotherapy, but it is to rule out metastatic disease. But still, if it's negative, you should go on with salvage radiotherapy.
Silke Gillessen: One of the problems is really that in a lot of guidelines, is this point 0.2 as a cutoff for PSMA PET, and that's a danger. Because people now are starting to wait, and I guess this is also a bit reflected in these results. And we have to go much more into it.
Bertrand Tombal: 0.2 has been there for a long period of time. We sent a word to hospitals when they put it for the first time. And it's because 0.2 is the clinically significant value. So there is a misunderstanding around the value of 0.2.
The guidelines never say that you define a recurrence by 0.2. What they say, and so far, it has not been proven the contrary, is that 0.2 is the significant value for the risk of developing metastasis, which is different from recommending radiotherapy.
In the end, it's a matter—do you believe in salvage radiation therapy or not? If you believe in it, you have to give it as early as possible because otherwise, we spoke a lot about that window of opportunity, you're just getting out of the window of opportunity.
Barbara Jereczek-Fossa: And I would say it is of importance for R1 patients, because R1 are those that 90% will be cured with salvage radiotherapy. R1 even so we don't wait for increasing PSA.
Silke Gillessen: OK. I see this is very nice because there seems to be a consensus on the panel at least. So here is the next question. So again, it's a biochemical relapse question in patients with EAU high-risk relapse and no negative PSMA PET. So what are you doing now?
So you have done the PSMA PET, you have the confirmed rising PSA. Are you monitoring or are you giving salvage radiotherapy? And there was a clear consensus to go for salvage therapy. Anyone to—
Barbara Jereczek-Fossa: So here, no PSA information you see here?
Silke Gillessen: No.
Barbara Jereczek-Fossa: No?
Silke Gillessen: No. It's just confirmed rising PSA.
Derya Tilki: Yeah, that's exactly what the guidelines also state. So really good result.
Silke Gillessen: OK. Let's go to the next one. Again, confirmed rising PSA. And again, high risk. Now is how are you doing this salvage radiotherapy? And we discussed that, I guess, at length. So it wasn't very clear. No consensus on that one, at least.
So 11% of the panelists would give radiotherapy alone. Then option two, 62% would give radiation therapy plus six months of ADT. Option three was radiotherapy plus long-term ADT of 24 months, 26%. And systemic therapy alone, nobody, quite nobody would give.
So again, I guess that's something for the radiotherapists. I'll start with you, Jason.
Jason Efstathiou: Sorry. Yeah, I think I voted number two here. But I think there is certainly some reason to think about potentially longer duration. We have RADICALS-HD, right? And that was the short versus long-term ADT comparison, with the MFS benefit to longer-term.
So I think we really want to see that trial published and review that in great detail. I think there is the potential for biomarkers, genomic classifiers, maybe AI, to inform duration in the future. And I'm hopeful to see studies look at exactly that question, not just the use of ADT, but its duration.
But for the time being, for the majority of patients, the way it's worded, I would be on option two. But let's hear from our other colleagues.
Silke Gillessen: Dan, you talked about it.
Daniel Spratt: Yeah. I mean, I showed you all those curves of ADT.
Silke Gillessen: Exactly.
Daniel Spratt: And I hope you were squinting as well as I was, as there's really almost no difference other than in the six versus 24 months. So I'm not really sure where option two comes from, why that's being recommended, other than it's what was commonly used in the other trials.
But to me, the bar to add a systemic therapy agent needs to be a survival benefit in this stage, like we do in localized prostate cancer. So I would still use radiation alone in the setting here. You have a negative PSMA PET. So you actually have a biomarker that is negative. So it's more favorable.
Obviously, you're not listing what the PSA is, but if you're going to do systemic therapy, the only trial that I guess you can point to is the RADICALS trial, which, even then, I still think it's just a T recovery delay as the MFS. And the OS is stone cold negative.
Silke Gillessen: European view, Barbara.
Barbara Jereczek-Fossa: Again, here, we don't have the PSA level. And with the data we have from meta-analysis SUPPORT and other studies, in that SUPPORT meta-analysis presented at ASTRO, I think last year, the cutoff was 0.8, 0.7 to add ADT to salvage radiotherapy.
So I don't see this value here. I think that, again, this could help to make a decision in between two and three or even one, two, and three.
Silke Gillessen: OK. Thank you. I think Dr. Fankhauser has a question or comment.
Christian Fankhauser: Yes. Thank you very much. Christian Fankhauser from Lucerne, Switzerland. PET was used—a very nice, but a strong term—called double trouble this morning. So surgery followed by radiation. And it's my understanding that the double trouble is coming from radiating the anastomosis, the sphincter.
So I wonder, we discuss this often in a patient with a very low PSA or a negative PSMA PET scan. And this question came up before slightly. Do you ever consider radiating first the pelvis, watching the PSA, and then the prostate bed, or the other way around or everything together?
We may have some risk factors where the recurrence is, but is it technically feasible, and is anyone using a sequential approach?
Barbara Jereczek-Fossa: I can start. It's technically challenging. I wouldn't do it. Because already, it's difficult to add the pelvic treatment after prostatic bed, especially if the patient underwent treatment in other centers. Because you have to have the plan, you have to do the dosimetry and so on. So I wouldn't do it. Maybe you have more experience with this kind of matching fields. So I would either do both or only pelvis.
Paul Nguyen: Yeah, I would agree for just the same reasons before, just that such a high proportion of these recurrences happen at the anastomosis that that would be the first place I would think. And as Barbara was saying, it is hard to match backwards from the pelvis back to the prostate bed after.
Daniel Spratt: And then RADICALS-RT in the early salvage arm. There was less than 1% grade three toxicity observed. So again, I think other than hematuria, I think there was 1%. So I just challenge, this is a very safe and effective therapy. Remember, this is not adjuvant. This is now in the salvage setting. Hopefully they've recovered.
Aurelius Omlin: So it's a good topic, Christian, that you raised because we have this question also. And as you can see, the panel is totally split. So this is a majority of patients, again, with PSA rise and pN0 after extended lymph node dissection. EAU high-risk. So rapid PSA doubling time. ISUP grade four or five. A negative PSMA PET. And you recommended salvage radiation therapy.
And we asked about the radiotherapy field. You see 18 of the experts also abstained because they didn't feel experts in choosing between prostate bed alone or the combination with the pelvic nodes. It's half-half.
And this changes completely in patients who have not had a pelvic lymph node dissection. That's the only change between the previous question and this question. Again, high-risk patients EAU definition. 14%. So it's a minority would only irradiate the prostate bed. And the rest 86% would irradiate pelvis and prostate bed. You all agree? Any comments?
Barbara Jereczek-Fossa: Yeah, it was quite easy, because here, the lymph nodes were not removed. So it's easier to decide the treatment field. I understand that here, it's not so easy. We have the evidence from the SPPORT trial and some other trials presented today.
I must say that after the SPPORT trial, we are also more often treating lymph nodes as well, not only prostatic bed.
Daniel Spratt: But a third of the patients on SPPORT had no dissection, did not have one. And in a secondary analysis from Bill Hall and others, those with four—actually it was over two lymph nodes. But over four lymph nodes or more, there was no improvement in outcomes in doing the nodal radiation therapy.
So in this case, it's an extended dissection as well as a PSMA PET. So.
Jason Efstathiou: Dan, can you maybe comment on what do you think is the additional toxicity of adding pelvic nodal treatment to prostate bed treatment?
Daniel Spratt: Historical nodal radiation, there was a meta-analysis of the 1990s trials. It was quadrupling of grade three side effects to add nodal radiation. In the contemporary trials, it's mostly grade one and two side effects and some hematologic side effects. But there's an increase in GI side effects. It's more minor. But if it caused no toxicity, I would just radiate my lymph nodes right now.
[LAUGHTER]
Aurelius Omlin: Let's move on.
Thomas Zilli: I think even in the SPPORT trials, it seems that the benefit is mostly for patients having a PSA below 0.35. So it means that probably if you have a very low PSA, you can stay just on your radiation of the prostate bed.
Silke Gillessen: OK, let's move on to the next one. So this is Paul, almost your question, 48. So if you now have patients with a confirmed PSA rise after radical prostatectomy without prior salvage radiotherapy, and again, EAU high-risk definition—PSA doubling time less than one year or ISUP grade four and five—and one to three positive lymph nodes in the pelvis alone on PSMA PET, what is your treatment recommendation?
And you see here, option one was SBRT of the positive nodes alone, there is almost no one. Some people, 20%, would radiate the whole pelvis plus/minus boost to the positive nodes. And 77% saw a consensus to do radiation therapy of the prostate bed plus the whole pelvis plus/minus also boost to the positive nodes.
Again, a radiotherapy question. So, Paul, maybe you want to say something, because it was quite your question?
Paul Nguyen: Yeah, sure. I am also option three here. I think this is a potentially curative patient. And again, most of the recurrences do happen in the prostate bed at the anastomosis itself. So it would be a shame to leave that out and not potentially cure this patient.
Silke Gillessen: Someone disagreeing?
Jason Efstathiou: Well, maybe I can pose another question. Let's say they had had prior radiation to the prostate bed and pelvis, and they now have nodes, right? And this was actually one of the questions that came in online as well. What would you be doing? Would you be SBRTing the nodes?
Paul Nguyen: Yeah, if they recurred in the prior pelvic field, then I would try to SBRT just that single node if possible, if the small bowel could tolerate it.
Barbara Jereczek-Fossa: We have quite a lot of experience on this kind of retreatment, and re-toxicity is extremely low now with SBRT. I would maybe add that, I don't know, there are very few people voting option one.
I still think maybe some selected patients, let's say elderly patients, 10, 20 years after surgery coming back with this kind of recurrence, I still think that you can discuss with them SBRT to the lymph node only. But it's, as I said, really a niche of the patients.
Silke Gillessen: Yeah. And probably not the high risk like PSA doubling time less than one year. But yeah. Thomas, you wanted, I think, to add something as well?
Thomas Zilli: No, I would just like to comment that in the OLIGOPELVIS but also in STORM, we included patients who previously were treated on the prostate bed. So I think we will have the answer concerning the biochemical disease control in one week.
But I think it's feasible. It's more challenging to combine both treatments. But finally, the toxicity, we demonstrated that it is no higher at two years. So I think it's quite feasible, clearly.
Aurelius Omlin: Now we move on to biochemical recurrence. One question, I think, only after radical radiation therapy of the prostate. And a question where you see absolutely no consensus. But something we see frequently, patients have had radical radiation to the prostate, plus systemic therapy, ADT plus/minus an ARP.
And the question was, at what point do we recommend imaging in case of a rising PSA from an NDR of let's say less than 0.2 in the context of a recovering testosterone? Do we wait classical definition PSA two plus nadir, option one. 36%. Do we image earlier at a PSA one to two in the context of a rapidly rising PSA? Or do we, irrespective of the PSA dynamics, image already at a PSA of one to two?
We did not have the option of imaging before one specifically in this question, but we didn't show all the questions that we voted on. I guess for the radiation oncologists it's probably clear, but we get nervous, and the patients get nervous.
Barbara Jereczek-Fossa: [INAUDIBLE] nadir plus two.
Jason Efstathiou: I actually think we need to revisit the definition of nadir plus two, especially in the era of next-gen imaging. And there is no doubt that I use imaging before that definition.
Aurelius Omlin: Even before one?
Jason Efstathiou: If, let's say, they nadired at 0.1 and it stood there for a while, and now it's going to 0.5 to 0.9, I will. And I find things. And I am considering local salvage. And part of me feels like in some patients, it may benefit to do local salvage a little sooner. So I'm definitely using it earlier. But love to hear what others are doing.
Barbara Jereczek-Fossa: There was—sorry, there's a lot of discussion at the nuclear medicine meeting in Seville last year. And they put really lower—less than one as the threshold to propose imaging. So I think that we are going there.
Thomas Zilli: Personally, it depends what you are looking for. So if you have already a PSA of one, a very rapid PSA doubling time, so probably the restaging is more to exclude some distant metastasis that can be treated with systemic therapies.
If you have a very slow PSA doubling time, probably this is the case for local treatment again. So I voted for two, but just based on this consideration to start systemic therapy before.
Daniel Spratt: What's the point, I guess, just—I rarely try to make things controversial. But what's the point of trying to image earlier? I mean, this is like—we have absolutely—I'd pick on the surgeons for having no data. We have just terrible data of local salvage therapy options.
If we're talking to do metastasis-directed therapy, of course, we have all of those trials. But I agree. And I think Tata Memorial has some great data at the PSAs of one to two. And I think Jason's right, we probably do need to revisit it. But it'd be nice to revisit it with the intent of we're going to do something evidence-based and get some trials in this setting.
Bertrand Tombal: Yeah. Because in real life, what we see with PSMA in that setting is that we do PSMA, many times we've got full color uptake. Then we do an MRI. Then we do biopsies. We haven't done that for years. And now suddenly, we start doing all these exams to people. Then we have a few cancer cells. We don't even know whether it's prognostic or not. So it's creating a lot of confusion.
So the first question would be really to demonstrate that there is any benefit for the patient to image it. Because that—I guess even more than the recurrence after surgery, it's creating a lot of confusion and anxiety amongst patients. Basically, we have no idea—it's very funny that the guideline says you should do a PET PSMA if you have at least a vague idea of what you're going to do next. So sometimes it's very complicated.
Barbara Jereczek-Fossa: We start to have more and more data on the local salvage treatment in patients after radiotherapy—either surgery or radiotherapy, SBRT, brachytherapy, and so on. Very nice also meta-analysis of retrospective data, so it is not high-level evidence.
But the tumor outcome is really the same constantly through these studies, and it's 50% progression-free survival at two years. So we are not very good in saving these patients. That's why I agree with the message from some of you. Maybe earlier imaging can help something here.
Aurelius Omlin: But it's a typical APCCC topic, where we don't have consensus, and we need to very carefully phrase the manuscript. Because clearly, we are voting for earlier imaging, but with what consequence.
Silke Gillessen: And I guess also maybe a good idea for the radio oncologists to try to redefine a good cutoff if possible. Because I think doctors like cutoffs. It makes life much easier. So only that we also can talk a bit about EMBARK. These were our questions about EMBARK.
For the majority of patients with high-risk non-metastatic hormone-sensitive disease, so EMBARK patients, what do you recommend for systemic therapy? And we asked it because now a lot of us are doing PSMA PET in these patients. So what are you doing when you see oligometastatic disease on PSMA PET?
And you see here, it's a bit all over the place. So option one is ADT alone intermittent. Option two is ADT alone, but continuous. So again, it's oligometastatic disease, but only on PSMA PET. Option three, that was the majority, ADT plus Enza intermittent. So as you have done in EMBARK.
Then number four was ADT plus Enza but continuous. And five, Enza alone. Six, only 1%, Enza alone continuous. So you see the AR antagonist alone wasn't really used a lot. What I found quite interesting and surprising.
And then if you have a negative PSMA PET, you see it's not actually changing so much. So, Neal, Bertrand, can I ask you?
Bertrand Tombal: To me, what's surprising is the very high penetration of option four. Because I tend to consider that—first of all, we discussed that when we did the question. It's very difficult to set up upfront are you going to do intermittent or continuous, unless you've got a very, very low response on PSA.
So probably we should have not mixed intermittent and continuous, which are two different questions. But once again, to me, the most important is that ADT alone is going down. Whether you use Enza alone or in monotherapy, like I said, you have aficionados like myself and people who believe we should not. It's going to take another five years before we have the answer.
To me, what's reassuring is that in the end, ADT alone, whether it's continuous or intermittent, is going down. Which is reassuring, which at least we believe in the trial we do.
Neal Shore: I would say that it's unfortunate that there's 18% who would just do LHRH either continuous or intermittent. There's no longer level one evidence that supports that if you believe in the EMBARK trial. So those are just wrong answers. And of course, everybody has access to all the therapy. And so I would think those 18%, they need to reassess.
As it relates to options five and six, the monotherapy, I think this is really early days and people need to understand they're not comfortable with it. T suppression has been part of our mantra, regardless of your specialty, for decades and decades and decades. And there's no doubt about it that T suppression has a lot of toxicity to it.
Enza monotherapy alone has a different safety adverse reaction profile. And what I was trying to highlight in my talk was that a lot of that can be potentially mitigated with preventative strategies. So I think that those numbers, five and six, if you were to ask this six months from now, a year from now, I think those percentages will go up significantly as patients—when patients have an option to make a decision.
Aurelius Omlin: April 29 to May 2, 2026, we will revisit this question no doubt.
Silke Gillessen: And hope there is a shift.
Aurelius Omlin: And the last question before we all go for a coffee break, and, Neal, you alluded to that question already. Now patients progressing on an AR antagonist monotherapy—we left it open at AR Enza, although we have data for Enza—without ADT, and now they have unequivocal radiographic progression. And they are not eligible for metastasis-directed therapy. What do we do? Continue the AR antagonist and start ADT. Option one. That's what 62% of the panel voted for.
Discontinue the AR antagonist and start ADT monotherapy. 12% or 26% voted for discontinuing the AR antagonist, start ADT plus an additional systemic therapy.
Silke Gillessen: Neal.
Neal Shore: Yeah. No, we're in a data-free zone here, as we oftentimes like to say. I chose option one. Some would argue that we want to continue to address all various clonal variations and subclonal variations, but this is a study that needs to be done. We need more data.
Aurelius Omlin: But do you have experience from patients on EMBARK? Or, Bertrand, what are you doing?
Bertrand Tombal: We have experience from the two monotherapy trials. And because, like I mentioned, it's always been very popular on bicalutamide 150. It doesn't work well. Actually, once again, it comes to me that maybe EMBARK, we should realize that the strong is not the ADT. The strong is the AR pathway inhibitor.
So when you had a strong and a weak, it works. If you had a weak on a strong, you shouldn't expect a lot. So we are putting together some data. It's not much better than Abi after Enza or Enza after Abi, whatever.
Aurelius Omlin: But for all future treatment considerations, you would have—
Bertrand Tombal: Yeah, that's the problem. The problem is they need to be castrated for next treatment. So it's more like a regulatory decision.
Aurelius Omlin: But you don't expect major activity of testosterone suppression.
Silke Gillessen: OK. Maybe that's a good topic for real-life data collection. So thank you very much. There is coffee outside. And we see each other in 30 minutes again here. Thank you very much.
Aurelius Omlin: For mHSPC.
Silke Gillessen: These were three questions. So what do you recommend for a patient with PSA persistence, and we defined it as more than 0.1 post-radical prostatectomy pN0 on extended PLND again and a negative postoperative PSMA PET provided the patient has regained continence?
And we ask that for three different scenarios. So the PSA is 0.2, and the patient didn't have any risk factors. So you see here it's about half-half of the panelists said, OK, let's monitor this patient and salvage therapy in case of further PSA rise. And 44% were for immediate therapy.
If you look at the scenario with the PSA much higher, 0.7, but again, no risk factors, you see there's a big change. So monitoring is only in 18% of the panelists would go for monitoring. And if you have no PSA defined, but two or more risk factors, it's even less of the panelists who would go for monitoring. So there, I ask you first to comment please on these results.
Derya Tilki: Yeah, interesting results. And it's really the point which is important, is that there are no risk factors because we cannot only look at the PSA but also at the risk factors. And there have been studies looking at the percentage of PSA value at persistence compared to the preoperative PSA.
And a patient, for example, with 0.2, could have had quite a higher PSA before surgery. And it could be at four weeks. So that would be a candidate for monitoring, like a lot of panel members voted. But at 0.7, it's quite clear that there is disease, and therefore the majority opted for immediate therapy, which I would also opt for.
Silke Gillessen: Thanks. Barbara, do you want to say something from the radiotherapy side, how you are managing these patients?
Barbara Jereczek-Fossa: Yeah, very interesting results. What I think is missing here to make a decision is maybe the doubling time. Because we have one value of PSA. And I think that it also would be good to know the next one, so then you can—it's easier to make a decision.
And definitely, patients, all of them are already, let's say, detectable PSA. So yes, we discuss salvage radiotherapy. I think I voted too.
Silke Gillessen: OK, perfect. If there are no questions—I don't see very well—then we go to the next.
Aurelius Omlin: So now we move on to the topic of biochemical recurrence after radical prostatectomy for the majority of patients. Something you will see very frequently at your MDT. Now, patients, we use this EAU high-risk criteria, PSA doubling time of less than a year, or ISUP grade four or five cancer.
And what do the experts recommend in case that there are no additional risk factors for local relapse as defined on the slide? Option one is salvage RT plus/minus systemic therapy—we didn't want to make it too complicated—as early as possible, as you heard today. Even before 0.2 PSA. Or wait until PSA is 0.2. That's option two. And do a PSMA PET if this informs your decision-making, or systemic therapy alone.
And you see here, 41% voted for as early radiation as possible. 57% voted for waiting until PSA is a bit higher and do a PSMA PET. And if there are additional risk factors, the picture changes a little bit. And now 63% would go for as early as possible radiation therapy. 37% would still wait until PSA 0.2 and do a PET.
Now, let's discuss this. We have a lot of radiation oncologists here on the panel. Maybe Thomas, what's your strategy in these patients?
Thomas Zilli: I think, of course, it depends on the PSA. But having a PSA doubling time less than one year, so we have a patient with a high risk. Of course, doing a PSMA PET-CT, we can detect where is eventually the disease.
But of course, we have just 40%, 50% of the patients having PSMA-positive lesions. So I think nevertheless, we have quite strong evidence to recommend early salvage radiotherapy in this setting. So I think that we can change the treatment management, and that finally, the indication to treat with salvage radiotherapy remains.
So personally, I voted for one, in this case independently of the presence or not of risk factors, but this is my opinion, of course. I don't know the other colleagues.
Aurelius Omlin: Is the PET even necessary? I don't know whether someone from nuclear medicine wants to comment. At a PSA approaching 0.2, does it make sense—do we waste resources if we go for a PSMA PET knowing that the chances of finding something is small?
Barbara Jereczek-Fossa: It's really—at least in Italy, it's not so easily available. So waiting list is one or two months for PET. So PSA would be already higher. So we don't ask for PET with this PSA level.
Jason Efstathiou: We have institutional data that suggests even in PSAs less than 0.2, there's up to a 50% finding on a PSMA PET. It's surprisingly higher than one might think. Some of the literature would suggest 30%. So I would—
Aurelius Omlin: A true positive finding, or?
Jason Efstathiou: Well, I mean, not necessarily biopsy confirmed, but not just kind of random little rib things either. But I guess I would say, and I'd love to hear from the other radiation oncologists on the panel, the data is supporting early salvage.
And early means the lower the PSA, the better. And I think we saw it throughout this morning's talks, that level might be even under 0.2, right? So I'm sort of surprised by these results, especially even the second one. Why isn't it closer to 100%? Why is it only 63%? It is the only potentially curative treatment still on the table. I don't know, any comments?
Paul Nguyen: Yeah, I would agree with you, Jason and Thomas and others, that we should start salvage radiation as early as possible. I do worry about the way option two is worded. That it could be misinterpreted about performing PSMA PET. That if the PSMA PET is negative, that we would then continue to wait until the PSMA PET turns positive before doing salvage radiation. So I think that's just important to clarify in the manuscript. I don't think we should be waiting for PSA PETs to turn positive before doing salvage radiation.
Ray McDermott: My concern there is you're denying people potentially curative treatment waiting on a result that will only affect 50% of them potentially. So I think it's a mistake. And I think you should just go ahead.
Derya Tilki: Yes. So I'm not a radiation oncologist, but I also have a comment. So in the EAU guidelines, PSMA PET-CT is recommended, but it shouldn't delay treatment, that's for sure. And I agree with Jason that a lot of these patients with high-risk EAU BCR do have a positive PSMA PET even below a PSA of 0.2.
And the sense of doing it is not to avoid radiotherapy, but it is to rule out metastatic disease. But still, if it's negative, you should go on with salvage radiotherapy.
Silke Gillessen: One of the problems is really that in a lot of guidelines, is this point 0.2 as a cutoff for PSMA PET, and that's a danger. Because people now are starting to wait, and I guess this is also a bit reflected in these results. And we have to go much more into it.
Bertrand Tombal: 0.2 has been there for a long period of time. We sent a word to hospitals when they put it for the first time. And it's because 0.2 is the clinically significant value. So there is a misunderstanding around the value of 0.2.
The guidelines never say that you define a recurrence by 0.2. What they say, and so far, it has not been proven the contrary, is that 0.2 is the significant value for the risk of developing metastasis, which is different from recommending radiotherapy.
In the end, it's a matter—do you believe in salvage radiation therapy or not? If you believe in it, you have to give it as early as possible because otherwise, we spoke a lot about that window of opportunity, you're just getting out of the window of opportunity.
Barbara Jereczek-Fossa: And I would say it is of importance for R1 patients, because R1 are those that 90% will be cured with salvage radiotherapy. R1 even so we don't wait for increasing PSA.
Silke Gillessen: OK. I see this is very nice because there seems to be a consensus on the panel at least. So here is the next question. So again, it's a biochemical relapse question in patients with EAU high-risk relapse and no negative PSMA PET. So what are you doing now?
So you have done the PSMA PET, you have the confirmed rising PSA. Are you monitoring or are you giving salvage radiotherapy? And there was a clear consensus to go for salvage therapy. Anyone to—
Barbara Jereczek-Fossa: So here, no PSA information you see here?
Silke Gillessen: No.
Barbara Jereczek-Fossa: No?
Silke Gillessen: No. It's just confirmed rising PSA.
Derya Tilki: Yeah, that's exactly what the guidelines also state. So really good result.
Silke Gillessen: OK. Let's go to the next one. Again, confirmed rising PSA. And again, high risk. Now is how are you doing this salvage radiotherapy? And we discussed that, I guess, at length. So it wasn't very clear. No consensus on that one, at least.
So 11% of the panelists would give radiotherapy alone. Then option two, 62% would give radiation therapy plus six months of ADT. Option three was radiotherapy plus long-term ADT of 24 months, 26%. And systemic therapy alone, nobody, quite nobody would give.
So again, I guess that's something for the radiotherapists. I'll start with you, Jason.
Jason Efstathiou: Sorry. Yeah, I think I voted number two here. But I think there is certainly some reason to think about potentially longer duration. We have RADICALS-HD, right? And that was the short versus long-term ADT comparison, with the MFS benefit to longer-term.
So I think we really want to see that trial published and review that in great detail. I think there is the potential for biomarkers, genomic classifiers, maybe AI, to inform duration in the future. And I'm hopeful to see studies look at exactly that question, not just the use of ADT, but its duration.
But for the time being, for the majority of patients, the way it's worded, I would be on option two. But let's hear from our other colleagues.
Silke Gillessen: Dan, you talked about it.
Daniel Spratt: Yeah. I mean, I showed you all those curves of ADT.
Silke Gillessen: Exactly.
Daniel Spratt: And I hope you were squinting as well as I was, as there's really almost no difference other than in the six versus 24 months. So I'm not really sure where option two comes from, why that's being recommended, other than it's what was commonly used in the other trials.
But to me, the bar to add a systemic therapy agent needs to be a survival benefit in this stage, like we do in localized prostate cancer. So I would still use radiation alone in the setting here. You have a negative PSMA PET. So you actually have a biomarker that is negative. So it's more favorable.
Obviously, you're not listing what the PSA is, but if you're going to do systemic therapy, the only trial that I guess you can point to is the RADICALS trial, which, even then, I still think it's just a T recovery delay as the MFS. And the OS is stone cold negative.
Silke Gillessen: European view, Barbara.
Barbara Jereczek-Fossa: Again, here, we don't have the PSA level. And with the data we have from meta-analysis SUPPORT and other studies, in that SUPPORT meta-analysis presented at ASTRO, I think last year, the cutoff was 0.8, 0.7 to add ADT to salvage radiotherapy.
So I don't see this value here. I think that, again, this could help to make a decision in between two and three or even one, two, and three.
Silke Gillessen: OK. Thank you. I think Dr. Fankhauser has a question or comment.
Christian Fankhauser: Yes. Thank you very much. Christian Fankhauser from Lucerne, Switzerland. PET was used—a very nice, but a strong term—called double trouble this morning. So surgery followed by radiation. And it's my understanding that the double trouble is coming from radiating the anastomosis, the sphincter.
So I wonder, we discuss this often in a patient with a very low PSA or a negative PSMA PET scan. And this question came up before slightly. Do you ever consider radiating first the pelvis, watching the PSA, and then the prostate bed, or the other way around or everything together?
We may have some risk factors where the recurrence is, but is it technically feasible, and is anyone using a sequential approach?
Barbara Jereczek-Fossa: I can start. It's technically challenging. I wouldn't do it. Because already, it's difficult to add the pelvic treatment after prostatic bed, especially if the patient underwent treatment in other centers. Because you have to have the plan, you have to do the dosimetry and so on. So I wouldn't do it. Maybe you have more experience with this kind of matching fields. So I would either do both or only pelvis.
Paul Nguyen: Yeah, I would agree for just the same reasons before, just that such a high proportion of these recurrences happen at the anastomosis that that would be the first place I would think. And as Barbara was saying, it is hard to match backwards from the pelvis back to the prostate bed after.
Daniel Spratt: And then RADICALS-RT in the early salvage arm. There was less than 1% grade three toxicity observed. So again, I think other than hematuria, I think there was 1%. So I just challenge, this is a very safe and effective therapy. Remember, this is not adjuvant. This is now in the salvage setting. Hopefully they've recovered.
Aurelius Omlin: So it's a good topic, Christian, that you raised because we have this question also. And as you can see, the panel is totally split. So this is a majority of patients, again, with PSA rise and pN0 after extended lymph node dissection. EAU high-risk. So rapid PSA doubling time. ISUP grade four or five. A negative PSMA PET. And you recommended salvage radiation therapy.
And we asked about the radiotherapy field. You see 18 of the experts also abstained because they didn't feel experts in choosing between prostate bed alone or the combination with the pelvic nodes. It's half-half.
And this changes completely in patients who have not had a pelvic lymph node dissection. That's the only change between the previous question and this question. Again, high-risk patients EAU definition. 14%. So it's a minority would only irradiate the prostate bed. And the rest 86% would irradiate pelvis and prostate bed. You all agree? Any comments?
Barbara Jereczek-Fossa: Yeah, it was quite easy, because here, the lymph nodes were not removed. So it's easier to decide the treatment field. I understand that here, it's not so easy. We have the evidence from the SPPORT trial and some other trials presented today.
I must say that after the SPPORT trial, we are also more often treating lymph nodes as well, not only prostatic bed.
Daniel Spratt: But a third of the patients on SPPORT had no dissection, did not have one. And in a secondary analysis from Bill Hall and others, those with four—actually it was over two lymph nodes. But over four lymph nodes or more, there was no improvement in outcomes in doing the nodal radiation therapy.
So in this case, it's an extended dissection as well as a PSMA PET. So.
Jason Efstathiou: Dan, can you maybe comment on what do you think is the additional toxicity of adding pelvic nodal treatment to prostate bed treatment?
Daniel Spratt: Historical nodal radiation, there was a meta-analysis of the 1990s trials. It was quadrupling of grade three side effects to add nodal radiation. In the contemporary trials, it's mostly grade one and two side effects and some hematologic side effects. But there's an increase in GI side effects. It's more minor. But if it caused no toxicity, I would just radiate my lymph nodes right now.
[LAUGHTER]
Aurelius Omlin: Let's move on.
Thomas Zilli: I think even in the SPPORT trials, it seems that the benefit is mostly for patients having a PSA below 0.35. So it means that probably if you have a very low PSA, you can stay just on your radiation of the prostate bed.
Silke Gillessen: OK, let's move on to the next one. So this is Paul, almost your question, 48. So if you now have patients with a confirmed PSA rise after radical prostatectomy without prior salvage radiotherapy, and again, EAU high-risk definition—PSA doubling time less than one year or ISUP grade four and five—and one to three positive lymph nodes in the pelvis alone on PSMA PET, what is your treatment recommendation?
And you see here, option one was SBRT of the positive nodes alone, there is almost no one. Some people, 20%, would radiate the whole pelvis plus/minus boost to the positive nodes. And 77% saw a consensus to do radiation therapy of the prostate bed plus the whole pelvis plus/minus also boost to the positive nodes.
Again, a radiotherapy question. So, Paul, maybe you want to say something, because it was quite your question?
Paul Nguyen: Yeah, sure. I am also option three here. I think this is a potentially curative patient. And again, most of the recurrences do happen in the prostate bed at the anastomosis itself. So it would be a shame to leave that out and not potentially cure this patient.
Silke Gillessen: Someone disagreeing?
Jason Efstathiou: Well, maybe I can pose another question. Let's say they had had prior radiation to the prostate bed and pelvis, and they now have nodes, right? And this was actually one of the questions that came in online as well. What would you be doing? Would you be SBRTing the nodes?
Paul Nguyen: Yeah, if they recurred in the prior pelvic field, then I would try to SBRT just that single node if possible, if the small bowel could tolerate it.
Barbara Jereczek-Fossa: We have quite a lot of experience on this kind of retreatment, and re-toxicity is extremely low now with SBRT. I would maybe add that, I don't know, there are very few people voting option one.
I still think maybe some selected patients, let's say elderly patients, 10, 20 years after surgery coming back with this kind of recurrence, I still think that you can discuss with them SBRT to the lymph node only. But it's, as I said, really a niche of the patients.
Silke Gillessen: Yeah. And probably not the high risk like PSA doubling time less than one year. But yeah. Thomas, you wanted, I think, to add something as well?
Thomas Zilli: No, I would just like to comment that in the OLIGOPELVIS but also in STORM, we included patients who previously were treated on the prostate bed. So I think we will have the answer concerning the biochemical disease control in one week.
But I think it's feasible. It's more challenging to combine both treatments. But finally, the toxicity, we demonstrated that it is no higher at two years. So I think it's quite feasible, clearly.
Aurelius Omlin: Now we move on to biochemical recurrence. One question, I think, only after radical radiation therapy of the prostate. And a question where you see absolutely no consensus. But something we see frequently, patients have had radical radiation to the prostate, plus systemic therapy, ADT plus/minus an ARP.
And the question was, at what point do we recommend imaging in case of a rising PSA from an NDR of let's say less than 0.2 in the context of a recovering testosterone? Do we wait classical definition PSA two plus nadir, option one. 36%. Do we image earlier at a PSA one to two in the context of a rapidly rising PSA? Or do we, irrespective of the PSA dynamics, image already at a PSA of one to two?
We did not have the option of imaging before one specifically in this question, but we didn't show all the questions that we voted on. I guess for the radiation oncologists it's probably clear, but we get nervous, and the patients get nervous.
Barbara Jereczek-Fossa: [INAUDIBLE] nadir plus two.
Jason Efstathiou: I actually think we need to revisit the definition of nadir plus two, especially in the era of next-gen imaging. And there is no doubt that I use imaging before that definition.
Aurelius Omlin: Even before one?
Jason Efstathiou: If, let's say, they nadired at 0.1 and it stood there for a while, and now it's going to 0.5 to 0.9, I will. And I find things. And I am considering local salvage. And part of me feels like in some patients, it may benefit to do local salvage a little sooner. So I'm definitely using it earlier. But love to hear what others are doing.
Barbara Jereczek-Fossa: There was—sorry, there's a lot of discussion at the nuclear medicine meeting in Seville last year. And they put really lower—less than one as the threshold to propose imaging. So I think that we are going there.
Thomas Zilli: Personally, it depends what you are looking for. So if you have already a PSA of one, a very rapid PSA doubling time, so probably the restaging is more to exclude some distant metastasis that can be treated with systemic therapies.
If you have a very slow PSA doubling time, probably this is the case for local treatment again. So I voted for two, but just based on this consideration to start systemic therapy before.
Daniel Spratt: What's the point, I guess, just—I rarely try to make things controversial. But what's the point of trying to image earlier? I mean, this is like—we have absolutely—I'd pick on the surgeons for having no data. We have just terrible data of local salvage therapy options.
If we're talking to do metastasis-directed therapy, of course, we have all of those trials. But I agree. And I think Tata Memorial has some great data at the PSAs of one to two. And I think Jason's right, we probably do need to revisit it. But it'd be nice to revisit it with the intent of we're going to do something evidence-based and get some trials in this setting.
Bertrand Tombal: Yeah. Because in real life, what we see with PSMA in that setting is that we do PSMA, many times we've got full color uptake. Then we do an MRI. Then we do biopsies. We haven't done that for years. And now suddenly, we start doing all these exams to people. Then we have a few cancer cells. We don't even know whether it's prognostic or not. So it's creating a lot of confusion.
So the first question would be really to demonstrate that there is any benefit for the patient to image it. Because that—I guess even more than the recurrence after surgery, it's creating a lot of confusion and anxiety amongst patients. Basically, we have no idea—it's very funny that the guideline says you should do a PET PSMA if you have at least a vague idea of what you're going to do next. So sometimes it's very complicated.
Barbara Jereczek-Fossa: We start to have more and more data on the local salvage treatment in patients after radiotherapy—either surgery or radiotherapy, SBRT, brachytherapy, and so on. Very nice also meta-analysis of retrospective data, so it is not high-level evidence.
But the tumor outcome is really the same constantly through these studies, and it's 50% progression-free survival at two years. So we are not very good in saving these patients. That's why I agree with the message from some of you. Maybe earlier imaging can help something here.
Aurelius Omlin: But it's a typical APCCC topic, where we don't have consensus, and we need to very carefully phrase the manuscript. Because clearly, we are voting for earlier imaging, but with what consequence.
Silke Gillessen: And I guess also maybe a good idea for the radio oncologists to try to redefine a good cutoff if possible. Because I think doctors like cutoffs. It makes life much easier. So only that we also can talk a bit about EMBARK. These were our questions about EMBARK.
For the majority of patients with high-risk non-metastatic hormone-sensitive disease, so EMBARK patients, what do you recommend for systemic therapy? And we asked it because now a lot of us are doing PSMA PET in these patients. So what are you doing when you see oligometastatic disease on PSMA PET?
And you see here, it's a bit all over the place. So option one is ADT alone intermittent. Option two is ADT alone, but continuous. So again, it's oligometastatic disease, but only on PSMA PET. Option three, that was the majority, ADT plus Enza intermittent. So as you have done in EMBARK.
Then number four was ADT plus Enza but continuous. And five, Enza alone. Six, only 1%, Enza alone continuous. So you see the AR antagonist alone wasn't really used a lot. What I found quite interesting and surprising.
And then if you have a negative PSMA PET, you see it's not actually changing so much. So, Neal, Bertrand, can I ask you?
Bertrand Tombal: To me, what's surprising is the very high penetration of option four. Because I tend to consider that—first of all, we discussed that when we did the question. It's very difficult to set up upfront are you going to do intermittent or continuous, unless you've got a very, very low response on PSA.
So probably we should have not mixed intermittent and continuous, which are two different questions. But once again, to me, the most important is that ADT alone is going down. Whether you use Enza alone or in monotherapy, like I said, you have aficionados like myself and people who believe we should not. It's going to take another five years before we have the answer.
To me, what's reassuring is that in the end, ADT alone, whether it's continuous or intermittent, is going down. Which is reassuring, which at least we believe in the trial we do.
Neal Shore: I would say that it's unfortunate that there's 18% who would just do LHRH either continuous or intermittent. There's no longer level one evidence that supports that if you believe in the EMBARK trial. So those are just wrong answers. And of course, everybody has access to all the therapy. And so I would think those 18%, they need to reassess.
As it relates to options five and six, the monotherapy, I think this is really early days and people need to understand they're not comfortable with it. T suppression has been part of our mantra, regardless of your specialty, for decades and decades and decades. And there's no doubt about it that T suppression has a lot of toxicity to it.
Enza monotherapy alone has a different safety adverse reaction profile. And what I was trying to highlight in my talk was that a lot of that can be potentially mitigated with preventative strategies. So I think that those numbers, five and six, if you were to ask this six months from now, a year from now, I think those percentages will go up significantly as patients—when patients have an option to make a decision.
Aurelius Omlin: April 29 to May 2, 2026, we will revisit this question no doubt.
Silke Gillessen: And hope there is a shift.
Aurelius Omlin: And the last question before we all go for a coffee break, and, Neal, you alluded to that question already. Now patients progressing on an AR antagonist monotherapy—we left it open at AR Enza, although we have data for Enza—without ADT, and now they have unequivocal radiographic progression. And they are not eligible for metastasis-directed therapy. What do we do? Continue the AR antagonist and start ADT. Option one. That's what 62% of the panel voted for.
Discontinue the AR antagonist and start ADT monotherapy. 12% or 26% voted for discontinuing the AR antagonist, start ADT plus an additional systemic therapy.
Silke Gillessen: Neal.
Neal Shore: Yeah. No, we're in a data-free zone here, as we oftentimes like to say. I chose option one. Some would argue that we want to continue to address all various clonal variations and subclonal variations, but this is a study that needs to be done. We need more data.
Aurelius Omlin: But do you have experience from patients on EMBARK? Or, Bertrand, what are you doing?
Bertrand Tombal: We have experience from the two monotherapy trials. And because, like I mentioned, it's always been very popular on bicalutamide 150. It doesn't work well. Actually, once again, it comes to me that maybe EMBARK, we should realize that the strong is not the ADT. The strong is the AR pathway inhibitor.
So when you had a strong and a weak, it works. If you had a weak on a strong, you shouldn't expect a lot. So we are putting together some data. It's not much better than Abi after Enza or Enza after Abi, whatever.
Aurelius Omlin: But for all future treatment considerations, you would have—
Bertrand Tombal: Yeah, that's the problem. The problem is they need to be castrated for next treatment. So it's more like a regulatory decision.
Aurelius Omlin: But you don't expect major activity of testosterone suppression.
Silke Gillessen: OK. Maybe that's a good topic for real-life data collection. So thank you very much. There is coffee outside. And we see each other in 30 minutes again here. Thank you very much.
Aurelius Omlin: For mHSPC.