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Alberto Briganti: Well, thank you very much, dear moderators, and thank you, Silke and Aurelius, for this very kind invitation to defend, in a way, surgery in the setting of high-risk prostate cancer as a part of a multimodal approach. These are my disclosures. So why should we consider surgery in this setting? In the lack of real evidence supporting the role of surgery in this setting, the main answer to me is to tailor proper approaches in patients with high-risk prostate cancer, which represents a highly heterogeneous patient population. So we really can tailor the approaches and aim for a treatment de-intensification in the setting, knowing that actually we can tailor proper use of postoperative treatments. Those opponents to surgery in this setting argue that surgery actually is toxic—a lot of side effects—and these patients should receive radiation therapy after surgery anyway, which is actually not the case. Now, as a surgeon myself, it's really tough to defend the surgery in this setting.

Why? Because even our guidelines have degraded the role of surgery in the setting of high-risk disease, strange to say. So basically, high-risk prostate cancer—the guidelines say in case of cN0 patients, no clear indications about the role of pelvic lymph node dissection; if you do it, you're doing the extended but no indication of that. Surgery is a part of multimodal approaches. I don't think this is the case honestly, and surgery has been deleted completely for the treatment of cN1 patients. And again, I don't think we have nowadays the evidence, at least not in the last year, to say we changed the guidelines for these. So one thing which I would like to highlight is actually if you stage patients with PSMA-PET and high-risk disease, you end up having approximately 20% of them with distant metastasis, whether nodes or bones. But still we have been treating patients with no negative imaging or negative imaging in general while these patients had already microdisseminated disease.

So what about surgery in the setting of RCTs? So we have three well-known trials that actually tested the role of surgery as compared to either active monitoring and radiation therapy or watchful and waiting. Can we derive information and counsel our patients in the setting of high-risk disease? Virtually not. And we cannot use these trials to meet for three main reasons. Why? First, some analyses are really weak because these were not specified upfront. Second, competing risks for mortality in the, for example, known PIVOT trial. Many of these patients were seriously ill. Third, because we don't have actually a good number of patients that were enrolled in these trials with the high-risk features. So we need to be very careful.

Again, treatment intensification or de-intensification. Patients with high-risk prostate cancer treated with surgery—in 30 or 35% of them, they end up having specimen-confined disease, negative margins, pT2, pT3, node-negative disease. And these patients honestly need to be observed. There is no need to give adjuvant therapy, and in absence of any therapy, the progression-free survival is really low, and many of these patients are cured in a way by surgery alone with excellent outcomes. Also in terms of 10-year biochemical recurrence rates. What about positive surgical margins? So the opponents of surgery say, "Listen, you have these patients who end up with positive surgical margins by definition," this is not the case. There is a significant decrease over time. Whether this is better patient selection or better use of surgery, we do not know.

And honestly, the vast majority of these patients has microfocal unilateral positive surgical margins, and this is not impactful for patient outcomes. These are mainly multifocal positive surgical margins, which in a high-risk series are actually found only in 5% of patients. Lymph node dissection. This is old story, which actually is nowadays very attractive and very hot. We have heard the fantastic lecture by Jochen saying that negative predictive value is highly dependent on the risks of having lymph node invasion upfront. Actually, patients with high-risk prostate cancer, they do have LNI rates of around 35%, one out of three. But of course the negative predictive value and sensitivity of PSMA-PET is highly dependent on the patient's features upfront, dropping significantly in patients with high-risk disease.

So should we skip, as Declan was saying, lymph node dissection in high-risk patients with negative PSMA-PET? I don't think we have the data to support that. What Declan says we have been skipping for several years is Declan's opinion. It's not supported at all by any evidence. So what about lymph node dissection? Well, there's a very, very, very criticized trial from Sloan Kettering—you've seen these slides already—no benefit on BCR, but benefit on metastasis-free survival in patients receiving extended lymph node dissection, and the two arms actually receive the same number of nodes more or less.

So I mean this trial is not yet published, but it's food for thought. And I believe that you have seen this slide already. The best benefit that these patients will derive is in the setting of node-positive disease or pathological node-positive disease. And guess what? PSMA-PET is missing a lot of microscopic pathological positive disease because it has intrinsic limitations at five millimeters more or less. So honestly, we shouldn't be surprised if we skip lymph node dissection and then this patient will have another recurrence even in patients with negative PSMA-PET. So why treatment intensification with surgery? I think this is key because now we are trying to actually understand who may be intensified or who may be de-intensified. And with surgery, we end up in having the same outcomes of radiation therapy plus long-term ADT with fewer treatments, with the same outcomes with less use of postoperative therapies or combined therapies.

This is evidence, it's not my opinion. So guidelines state don't give adjuvant ADT in pN0 patients, don't even give adjuvant ADT in pN1 patients based only on the Messing trial. So very weak recommendation. Second, can we use the ADT plus ARTA again in these patients, even in the perioperative period? Honestly, there is not yet big evidence. The PROTEUS trials will be released soon, but not yet available. There are many phase 2 studies showing that if you combine the two approaches, you may decrease tumor volume, which might be associated at least with biochemical recurrence. But yet we don't have any data supporting the role of intensified perioperative approach in this setting. What about chemotherapy? Actually, no clear indication of a real benefit of perioperative chemotherapy. So everything which we have given on top of surgery actually kind of failed to be associated with outcomes.

What about adjuvant radiation therapy? We all know about the three trials of adjuvant versus early salvage which change significantly our practice. The guidelines anyway, and I'm citing the EU ones, still indicate the possible offer of adjuvant radiation therapy in patients with adverse features, pN0 or in some patients with pN1 disease. But the reality is this one: we have been decreasing significantly the use of postoperative adjuvant radiation therapy +/- ADT. This is the reality. And in our centers, only very few of them are receiving adjuvant radiation therapy based on these studies, even though these studies are flawed by the limited number of patients with aggressive features included. What about cN1 patients? The guidelines don't even mention any longer surgery in this setting as compared to last year. So my impression and my guess was that in this year, big trials came out saying no surgery in this setting—no big trial. So the guidelines have changed based on what? Nobody knows.

So basically, the guidelines use and recommend the use of radiation therapy plus ADT plus abiraterone for cN1 disease. They don't consider surgery any longer without any adjuvant comparative study between surgery and radiation. The fact that abiraterone is improving survival as compared to ADT plus radiation therapy versus ADT plus radiation therapy alone does not exclude surgery from these patients. I believe these patients will inevitably become impotent or incontinent. Again, completely wrong. And these are the rates of nice consecutive and contemporary series of radical prostatectomies done in high-risk patients. The rates of urinary functional recovery is 90%. Honestly, it's way higher than patients treated with open approaches and is higher than patients treated at lower volume centers. We need to centralize many of these patients if we want to optimize outcomes.

What about sexual function? Of course, we have an increase in sexual function. This increased up to 20 RCTs. And of course, this again shown by this study coming from high-volume centers, but honestly to me, three years hormones or hormones plus something else is not doing good for erections either. So basically, surgery versus radiation therapy is an old debate. I don't want to go into that. There is no way we can do comparisons and good comparisons between surgery versus radiation means of biased retrospective series where patient selection is huge. So we need RCTs, and this is the only one to my knowledge that is testing cancer-specific survival as outcome between surgery versus radiation therapy. And this was my last slide. I really thank you all and thank you again for this nice invitation. I will invite you myself to our scientific retreat, Uro-Oncology at San Raffaele Hospital next December. Thank you.