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Zach Klaassen: Hi, my name is Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined for the UroToday discussion with Dr. Costas Zamboglou, who is a radiation oncologist at the University of Freiburg in Germany. Costas, thanks so much for joining us today.

Constantinos Zamboglou: Yeah, thank you very much for the invitation. It's a great pleasure. You are doing a great job, and it's a big honor for me to present.

Today I want to present our work called "PSMA-PET/CT Improves Outcome after Salvage Radiotherapy for Recurrent Prostate Cancer after Surgery." What is very important to mention is that we have quite nice data coming from [inaudible 00:00:39], coming from Los Angeles, showing prospective studies that we have a very good detection rate for PSMA-PET/CT imaging for patients with recurrent or persistent disease after surgery. What we have learned is that the detection rate increases with the PSA and that the PSMA-PET has a substantial influence on our treatment. This is what we know. However, what we don't know is if this impact on the treatment, on the management of our patients, really is influencing our treatment outcomes. And this was the main aim of this study. And what I will show you today is first a little bit about the methodology, then our key results, and I will close with a summary.

Regarding our methodology, we used two separate patient databases. Database one is from a quite famous prospective phase 3 trial, the SAKK09/10, which used non-PSMA guided salvage radiotherapy from 28 centers in three countries. They included 344 patients, and the follow-up was quite long, 75 months. We used also another database from an observational retrospective database from 11 centers in five countries. These patients, all of them, had PSMA-PET guided salvage radiotherapy. We had a quite big database with 1,500 patients, and the follow-up was 31 months.

What we did was pool these databases and then excluded patients. We excluded patients with pN1 or pNx disease in surgery. We excluded patients with R2 resection or unknown resection status. And we excluded patients with high PSA values before salvage radiotherapy. Why did we do this? Because there are some studies that suggest giving androgen deprivation therapy in parallel to salvage radiotherapy when the PSA is higher than 0.5 or 0.7, so we wanted to ensure that ADT was mainly given because of the PSMA-PET findings in our cohorts, and of course, patients with missing information in the stratification variables.

In total, we had 770 patients, and then we performed treatment weighting with entropy balancing weights. What we did is we simulated a prospective study design by considering the age, the ISUP grade, PSA before salvage radiotherapy, the T stage, and whether the patients had PSA persistence or recurrence. As you can see here, it was very nicely weighted to cohorts. So the red is before weighting, the blue lines are after weighting, so it was very well-balanced.

And what we see here at the end of the day, in the SAKK group nobody got ADT and there was no pelvic radiotherapy performed. However, in the PSMA group, we gave ADT in cases of pelvic lymph node or local recurrence on PET, or of course, we irradiated the pelvic lymph nodes in case of positive PET findings. So this was a PSMA-PET based treatment approach. And at the end of the day, what you can see here, we had in this group nodal recurrences in nearly 100 patients. We had elective pelvic lymphatic irradiation in 120 patients, and irradiation of pelvic lymph nodes in 103 patients, and a significant amount also received ADT.

And here is the most important result of our study regarding PSA relapse or death. You see a significant benefit for the PSMA-PET treated patients, here the yellow line. They had a significantly lower amount of PSA relapses. And we had a closer look at different time points, and what we observed here are the hazard ratios that this benefit was significant in the first year and also in the second year after salvage radiotherapy, but not in the third year. Here you see the hazard ratios and the P values. We also did two sensitivity analyses. We excluded patients with ADT and we excluded patients without radiotherapy to the prostatic fossa, and very comparable results were observed.

Coming to another finding, what is very important I must say, is the recurrence patterns. We were looking at where the disease occurred after salvage radiotherapy. And what you can see here, this is the most important part highlighted in red, that in the PSMA-PET staging group we had significantly fewer patients with nodal pelvic recurrence, which is obviously based on this very targeted approach of irradiating the pelvic lymph nodes based on PET. And this is very important to also keep in mind for later. And we also looked at the cumulative incidence of metastasis of death. So on the metastasis-free survival, and here we didn't see any significant differences.

Now comes a big but, because we had a look at how the patients got restaged after salvage radiotherapy. And here it is clear that in the PSMA groups, so the patients who got PSMA-PET guided radiotherapy, nearly all of them or most of them by far were restaged with PSMA-PET. So metastases were detected really early, and in the SAKK group we didn't have this information, but obviously a lot of these patients weren't restaged with PSMA-PET. So we don't know if this not significant metastasis-free survival is just because of the more modern restaging used in our patient cohorts.

Coming to the summary, we had well-balanced cohorts of patients in our study. There are ongoing randomized trials, at least two, comparing PSMA-PET guided salvage radiotherapy with non, however they had fewer patients than we had. And coming to the conclusions or the main results, the implementation of PSMA-PET imaging leads to better short and midterm biochemical control.

What is the most possible reason? I would say, also considering the relapse patterns, we have better coverage of the PET-positive pelvic lymph nodes. However, it's just midterm. After two years this effect diminished in our study and maybe we should escalate systemic treatment for some of these well-selected patients to also get better long-term disease control. And we had no impact on metastasis-free survival, which we already discussed. I think this is because of the usage of PSMA-PET imaging for restaging. However, what we have to say, the follow-up in our group was just approximately 30 months. And of course, we need longer follow-up to really determine if the implementation of PSMA-PET is also increasing the overall survival of patients.

Thank you very much for your attention.

Zach Klaassen: Costas, thanks so much for sharing that data. Very fascinating. I like how you brought in the two cohorts with the SAKK cohort as well as your own retrospective cohort.

There are a couple of interesting discussion points. One thing I want to hit on is we're seeing patterns of disease that we're not used to seeing at very low PSA. So all of your patients had a PSA less than 0.5. Maybe just speak to the detection rates at this low PSA that you guys found.

Constantinos Zamboglou: Yeah, the detection rates for patients between 0.1 and 0.5 were around 30 to 50%. So I would say a very nice perspective study from UCLA, for example, showed a detection rate of approximately 40% of the patients, which is quite a good amount I would say.

Zach Klaassen: Yeah, absolutely. And I think you made a good point in your summary about how we don't have overall survival data. These endpoints take years to develop, but just talk about the conversations you have with your patients in the clinic.

Patients want to know, with the best technology, which right now obviously is PSMA-PET, how do those discussions go? Even with positive studies, so their PSA may be 0.4, they've got a couple of lymph nodes, you know where that disease is. Talk about the patient perspective of knowing exactly where their disease is and going forward with treatment from there.

Constantinos Zamboglou: Yeah, so you mentioned a very important point. I mean, I always would like to see as a patient what I'm facing. And somehow strange, you had surgery, you thought, "Oh fine, I'm cured." But then suddenly the PSA rises, and this is very abstract for the patients. When you tell them, "You have a PSA relapse," they don't understand it, most of them because it's somehow strange. There's just a laboratory value rising. And of course, what all the patients then ask is, "Where is the tumor? The prostate was removed, where do you find it?"

And for us, as radiation oncologists, when I was a resident before the PSMA-PET era, it was somehow hard to explain to them, "Yeah, well, we don't know but will irradiate your prostatic fossa now for two months." And then they ask, "Yeah, but how do you know that it's there?" And then we always have to tell them, "Yeah, we don't know. But historically we know that approximately 70% of the relapses are within the prostatic fossa," and so on and so on. But of course I would like to know, as a patient and as a physician, where's the tumor.

Zach Klaassen: Yeah, absolutely. Great answer. I think you mentioned we have some great prospective data coming, we'll obviously look forward to that. Maybe just a couple of take-home points for our listeners based on your study.

Constantinos Zamboglou: I would say the take-home point is we should learn based on PSMA-PET where to escalate, but also where to de-escalate, because it doesn't make sense to use PSMA-PET and at the end of the day treat our patients like we have treated them before. I would say first, when you have a positive PET, I would use it, especially when they are positive lymph nodes, to irradiate the lymph nodes with radiotherapy to boost the positive regions in the pelvis, but also really consider systemic therapy, maybe 24 months. Because what we see in our study is that this treatment escalation wasn't for the long term. So I would say, and we have the RADICALS-HD data that we can give 24 months, and I think the PET, the pelvic lymph nodes and PET are very nice surrogate parameters for this kind of escalation.

But now comes a big but, we could also use the PET information for de-escalation. For example, if you have a patient who had prostatectomy five years ago, ISO 2 or 3, and a PSA of 0.3, and just a local recurrence with a PSA of 0.3 or something in the fossa, for this patient, I personally would just irradiate the fossa and boost this local recurrence but not give ADT. This is my personal opinion on how to use this tool.

And lastly of course there's a big question, what to do with the PET-negative patients. I think there are a lot of quite interesting studies ongoing. Personally I don't like it to not irradiate, so I would say, okay, we can wait until the PSA is 0.5. But if the PSA is above 0.5, personally I recommend doing the salvage treatment to irradiate the fossa because we know that as higher the PSA gets, the worse the outcome.

Zach Klaassen: Excellent. Costas, thanks so much for your insight today. We enjoyed hearing your presentation about your ESTRO 2024 data. Thanks so much again.

Constantinos Zamboglou: Thanks, bye.