Alberto Briganti: Thank you very much. I would like to thank you all, and thank, of course, Silke and Aurelius for this kind invitation. It is a true honor and a pleasure for me to be here. I'm a surgeon. I read a lot of the things about medications, radiation therapy, almost nothing about surgery. So I'm trying to give you some insights about what I see might be the future of the treatment of localized prostate cancer. I also learned from you something which is very important. Because I believe that you save 99% of my presentation, saying that absence of evidence is not evidence of absence. As surgeon, we live in an era of absence of any evidence, in many things that we do. So we are not good in that. Despite that, believe it or not, or like it or not, surgery is the most widely treatment used for locally advanced prostate cancer. Not in UK, certainly, not even a patient randomizing STAMPEDE trial so far. Receiving radical prostatectomy, nobody knows why.

So what I see in the future, in terms of intensification of multimodal therapy? I believe that we will treat more and more patients in a tailored way. We cannot go for one fits all approach. I think it's completely incorrect and I think we have now the weapons to use to tailor treatments. In surgery, just to give some examples, as surgeon we have been killed by studies made in the past. Potentially testing the role of ADT prior to surgery, but we know that all virutally failed. No impact of any kind on our clinical endpoints. So the guidelines say don't give ADT prior to surgery, even in high resetting, which is correct. Now we actually are assisting to ours, a new revival of the neoadjuvant therapies. With ideas of actually giving more intense androgen deprivation therapies and maximizing the blockade of testosterone production within the tumor.

But we have to be careful because many of these studies are mainly phase two with limited number of patients and mainly assessing the role of treatments in decreasing tumor volume. We do not know yet, what the decrease in tumor volume is associated with important high clinical endpoints. However, like going from the neoadjuvant therapy first and surgery second, might be also a good way to test an impact. That specific therapy, in terms of tissue analysis. And of course, there has been some studies that show something which need to be tested in properly prospective studies. There's a study that actually randomized patients to leuprolide plus enzalutamide plus or minus abiraterone. Actually, the rate of patients that had complete response in terms of pathological outcomes, were doubled as compared to those not receiving abiraterone. It was also interesting to know that patients with ERG positivity or PTEN loss were those who were at lower response to treatment.

In a way, we can start thinking, which are the predictor to giving therapy, which might be given also prior to surgery? There is a lot of studies out there. These studies, some of these are phase three already. They are testing the use of other molecules in the setting of neoadjuvant therapy after, before radical prostatectomy. We also are doing a study using immunotherapy. Like giving a combination of ADT plus premrolizumab prior to high-risk prostate cancer. Then we are testing the pathological response, and again in these neoadjuvant studies, mainly pathological response is the main outcome. Again, we are very cautious because we don't know yet whether this confers also survival outcomes, to our advantages. The other ideas when we go for surgery, where I see the future is the possibility to tailor treatments. Actually we can also avoid the risk of over treatment of these patients. Giving too many treatments in that cancer, which might not deserve to be treated so heavily. We might use in the genomic information, both for prognostic indications but also for predictive indications. We can use, for example, this study that's been published, the Decipher test, by any other signature to predict those patients. We responded, why do you want radiation therapy?

For unknown reason, again we are moving from adjuvant radiation therapy to [inaudible 00:04:01] adjuvant radiation therapy. There is also prospective studies that are testing whether using our genomic signature in the prostate can also impact patient management. Again, these are very weak endpoints. We should know whether these kinds of approach is able also to improve patient outcome. There are studies going on which will give an answer quite soon. Not only the radiation therapy, but starting from surgery and treatment of local advanced prostate cancer. We may also have signatures, we may predict the response to ADT. We all know that the use of adjuvant ADT is very limited after surgery, in a very limited subset of patients. But still there might be patients in which we may test the novice signatures and you may give additional therapy, based on pathological report PSA after surgery and the combination of genomics in general, like this case.

The other thing which I see a big future about is the imaging guided surgery. Of course we all know about PSMA PET. Honestly, we talk a lot about PSMA PET. Maybe I believe a little bit too much. The thing is that when you go for PSMA PET, everything needs to be fantastic, it's done. The problem is that when you have a histological confirmation of what you look at you may have some decent point in the results. I think we should learn from surgical series. Because you go for PET prior to surgery, prior to radical prostatectomy and look at the sensitivity that you find at the node level analysis. Not actually looking at patient base analysis, but actually node base analysis. You find the sensitivity is quite low, it's 40%. That you miss a lot of positive lymph nodes prior to surgery if you scan these patients, even in higher setting with PET PSMA.

The vast majority of these men, indeed they have micrometastasis disease. Which is still undetectable, even by the best PSMA PET done in the best centers worldwide. Now with surgery we are trying to explore the possibility to use PSMA combined to technician, to actually direct our surgery towards those nodes. Which are found both in PET but also interoperatively. This has been tested in men undergoing salvage lymph node dissection for recurrent prostate cancer. But again, while we are moving towards early disease. So we are now testing the role of this kind of approach, prior to initial extent the lymph node dissection. Novel tools to improve local control. I think this area, when we are working a lot, you can see from this video, you can actually are... In the process now that you can modulate and overlap the imaging from an MRI to your anatomical field using robotic assisted radical prostatectomy.

You may actually control the side, the extent of the possible invasion of the tumor outside the prostatic capsule. Or you may increase the rate of positive surgical margin. Decrease the rate positive surgical margin after surgery, by doing so. Last comment that I want to say is the centralization of care. When you talk about locally advanced prostate cancer, we cannot treat that given patient, in a given center, in the middle of nowhere. These patients should be centralized to high volume center. This has been recently, and in many publications already demonstrated. We should treat these patients in high volume centers. So what is the future? I mean, I found some hard time to convince my two daughters, that we as surgeons are not that bad. We can randomize also, not only removing organs. The reason our trial, which is going on, which will give us the answer about surgery restoration radiation therapy, is the SPCG-15. This is the only trial we should look at, when we counsel our patients between surgery and radiation therapy. Thank you very much for your attention.