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Alberto Briganti: Thank you very much and again, welcome you all. Again, a big thank to our colleagues coming from abroad and to all of you coming here today to listen to this day dedicated to treatment and advances in the genitourinary malignancies. It's also a big honor for me to be introduced by my mentor actually who trained me over the last 15 years or so.

I have been asked to review what have been the main advances in prostate cancer research over the last 10 years, which is a main topic or a huge task because this is one of the fields where we have the major advancements over the last 15 years I would say. I would focus my presentation on three main topics. One is diagnostic advances; the second one, the intensification therapies; and the third one is the treatment of metastatic prostate cancer. Mainly what we have assisting is novel, new and strong database on randomized control trials, but still, many questions still remain unanswered.

What about imaging? We have assisted over the last 10 years to imaging revolution. And imaging actually came in different diagnostic processes of prostate cancer, not only diagnosis but also staging our mainly referring to MRI and PSMA PET. If you look at the guidelines, which is our backbone, when we do actually treat patients with prostate cancer, we always refer to EAU guidelines which are those based on the highest level of evidence based on systematic reviews, meta-analysis, and using the correct grade of recommendations. And we see over the last 10 years that we changed significantly in terms of recommendation for MRI. MRI has be included in the guidelines in 2014, suggested for patients with initial negative biopsies and candidate for repeat biopsy.

Now, MRI is recommended as triage test for all patients coming in with elevated PSA with a suspicion of prostate cancer. What we know about MRI? There are certainties. So when we introduce MRI in our clinical decision-making process, we certainly decrease the number of unnecessary biopsies. We decrease the rates of insignificant prostate cancer detected. These of examination in experienced hands. It has high negative predictive value which is maintained over time. And of course, when we do biopsy we should always combine targeted versus systematic biopsy upfront.

However, there are grey zones. The grey zones of MRI are huge and are mainly referred to experience variability of readers and quality of images, which makes this imaging approach quite heterogeneous in terms of diagnostic properties. And more importantly, as these step towards MRI changed outcomes of patient prostate cancer, this is still being question mark. When we talk about negative predictive value and positive predictive value, we know that MRI is a high negative predictive value, but what about positive predictive value? Which is extremely low, actually.

We have many examination, we are still false positives and we are doing too many biopsies because of indications for biopsy given the pilot score. But if you look at the pilot score of four, you have positive predictive value as low as 40%. And this is overall including patients receiving MRI by different centers with different expertises. What we do now every day in San Raffaele Hospital is that we review each single MRI that is coming in with patients with a diagnosis or with a suspicion of prostate cancer. We ask our audiologists to re-review all images, and we found something which is interesting in more than two thirds of the patients would coming in with a pilots four, they are downgraded to pilots 1 to 2 which means no biopsy at all. Basically, in a third of these patients we change our indication for biopsies.
And if you look at those guys receiving MRI revision versus not receiving MRI revision, there is a significant difference in terms of clinically significant prostate cancer. So quality matters and experience of radiologists is key to give the proper indication of a prostate biopsy. However, there are some issues with MRI guided biopsy and these issue is mainly due to overgrading. Indeed, when we look at the certain lesions seen at MRI like pilots four, pilot five, we actually stick the needle into the lesion, which is what we do every day. The problem is that we might overgrade that specific prostate cancer lesion because actually we pick the lesion very well but we undersample what is outside the index lesion sometimes and actually we sometimes give overgrading because we oversample the index lesion and we undersample what is outside the English lesion.

And so we are trying to understand which is the best systematic biopsy schemes to couple targeted biopsy. And this has been reported in this very provocative editorial or brief correspondence that has been published by Dr. Vickers, as you know is a worldwide famous biostatistician involving prostate cancer and it is some statistical modeling kind of complex ones but actually a couple two different chords of patient. One receiving MRI targeted biopsies, the other one receiving prostate cancer screening and doing a sort of simulations. Actually, he was able to demonstrate that even if we put the best case scenarios for MRI, like MRI able to pick up all significant cancer, those lethal ones. We do have a number needed to diagnose of 89 to prevent one prostate cancer death. In a way we are also over diagnosis prostate cancer even by using MRI and even by using MRI targeted biopsies.

What about PET? PET has changed the way we are managing prostate cancer but we need to be very careful because things seems to be easier but they are way more complicated because the main question is what to do when we have a positive test. And these questions are mainly unanswered nowadays, but still there is a trend of prescribing PET PSMA, PET for all patients coming in for prostate cancer staging. And even though this is not included in a guidelines, a recent consensus meeting show that 80% of experts involved in a panel consultation, they do prescribe PSMA PET upfront as primary staging even though this is not highly recommended or truly recommended by the current guidelines. The real question is what to do with a positive PET because all the studies have been base of conventional imaging and now we have a patients coming in with a positive PSMA PET which is not detected by conventional imaging. What to do?

And the risk here is to base our decisions too much on positive PET and then maybe to undertreat the primary in patients with disseminated diseases. And we now have the evidence even based on conventional imaging, the treatment of the primary matters in prostate cancer if we are dealing with oligometastatic disease. And then PSMA PET has also false positives and this is also very true in patients receiving for example fluoride, fluorinate agents. I have seen here Professor Fantin coming in and he will talk about this differences between gallium and fluorinate PET and PSMA PET. And we now are moving or have moved to towards fluoride PET, which actually is not good because it has lots of false positive findings especially in the ribs. We are now changing our indications bade of something which we consider being state of the art for prostate cancer staging, but it's not.

And we are still need to do some secondary confirmation for these lesions with increased costs and reduce and minimization of somewhat the resource that we have nowadays. What about in the recurrent setting? Well, PSMA PET has indeed a big role in the recurrent setting and the guidelines are very clear in saying, "When you have patients with recurrent disease after either radical prostatectomy, radiation therapy, you need to give PSMA PET in all patients." Very clear. No other things, just do imaging and then you decide upon what you see imaging. And here comes the problem because sometimes you see something at PET in the oligo recurrent disease maybe or mainly in the early recurrent setting you see some spots and you say, "What to do?" The natural consequences of these is to give metastases directed therapy, so to irradiate the mets or to remove the metastases.

And we explored these, we were actually the first to explore these in the so-called salvage lymph node dissection setting. Then we go back to the evidence, "Are we doing the right thing?" Well, yes or no? I mean all these story of metastases director therapy for recurrent disease detected by PSMA PET is based on 150 patients. Not even those. These are three phase two, not even phase three prospective randomized trials that actually showed that if you go for metastases directed therapy in a prospective randomized manner, you actually may decrease the initiation of ADT and you may increase the rates of cancer control early after therapy.
But what about long term? No data about that. We are actually changing our attitude base of a hundred patients randomized in three phase two studies. We need to be very careful, and the guidelines are also very careful and say that if you go for metastases-directed therapy, you need to do inappropriate study, which must be in a way at least approved by your local ethical committee. Despite these, the trainers left the station because then we go to the back, to the experts and the experts say, "Well, why not?" In 80% of the cases they do prescribe metastases-directed therapy even without strong evidence. And these are the so-called major experts in prostate cancer that every year meet in Lugano for the APCCC meeting. Something to think about for the future.

Once we have PET and we have MRI and we detect prostate cancer, in many cases we do actually have the diagnosis of high-risk disease. And one of the main topics over the last years have been, what we do? What do we do with high-risk prostate cancer? How do we manage that? And of course, we have two options. One is surgery and the other one, radiation therapy. I'm not going into the deepest which is useless to do either surgery or radiation therapy. What is best? That's not the issue. The issue is that whenever you do something, you have to do that in the right and proper way. And over the last 10 years we have seen that the radiation therapies have been way better than us in producing high level of evidence. They de prospective randomized trials and they actually have been able to show that if you go for radiation therapy, that should be a combination therapy with long-term ADT. That's we all know.

But recently for patients with very high risk disease by STAMPEDE group and we are honored to have you, Doctor Clara, as one of the main actors of these great collaboration of great group study. They show that if you add abiraterone two years together with long-term ADT, together with radiation therapy in patient with either CN one disease or very high risk prostate cancer, you actually have better outcomes. What about surgery? Surgery has been different. Over the last years, we tested everything together with surgery, new adjuvant chemo, adjuvant ADT, new adjuvant ADT, new adjuvant novel agents, but all failed. It's not that it was a real failure to make a long story short, but actually there was disappointing results. Nowadays, guidelines do not recommend any systemic therapy coupled with surgery except for patients with not positive disease.

And the same might apply to radiation therapy. When I started to deal with prostate cancer, we overtreated many patients with locally advanced prostate cancer with adjuvant radiation therapy and then we realized that many of these patients were overtreated because many of these patients would've never occurred even without adjuvant radiation therapy. And eventually, we did have the trials and these big three trials, phase three prospective randomized, they clearly showed that if you compare adjuvant versus early salvage radiation therapy, there is pretty much no difference. The clinical endpoint in this case would progression. We are not talking about survival, but still their curves completely overlap. The urological community has moved over the last 10 years from adjuvant radiation to early salvage radiation therapy going in the direction of the intensification of therapies when patients are treated with radical prostatectomy. However, a word of caution, because all the three trials I showed you with the overlapping curves, actually they included very favorable patients.

Those patients with seminal vesicle invasion only 20%. Patient with no positive disease, pretty much zero. Patient with high lesion score eight to 10, 20%. This is not actually applicable, strictly speaking to what we see nowadays, at least in this hospital when we treat many patients with that local advanced prostate cancer.
The third big chapter is metastatic disease and we have a big revolution in this setting. When we started 10 years ago, 2012, there was mainly ADT, then we played a bit with androgen deprivation therapy together with bicalutamide and we did some form of combination therapies, but it was mainly ADT alone all together with bicalutamide. And things change significantly. And this is one of the biggest change that we've assisted over the last 10 years because now when we are dealing with de novo metastatic disease, we do have a lot of options.

And this is not only ADT alone, it's not any longer ADT alone, it's ADT plus chemotherapy, which is docetaxel or abiraterone or apalutamide or enzalutamide. Now, we are trying to understand which is the most appropriate therapy for which patients, but still we have these options which are anyway not the only ones because now we even entered in the tripod therapy era. It's not ADT plus something else, it's ADT plus a couple of something else. It's in terms of docetaxel plus abiraterone or docetaxel plus darolutamide or docetaxel plus enzalutamide. This is what we have nowadays available, which is a huge step forwards as compared to 10 years ago. Different options, we need to select the proper patients for the product treatment. And so some of us, like Dr. Sweeney, I borrowed this slide from him and would like to thank him for this great summary.

We are trying to understand which would be the best patient for the best option. We actually divide patients according to volume of the disease, according to the status of the disease, de novo versus recurrent, of course, performance status and of course patient preferences. But still we are trying to modulate these different therapies according to each patient profile. But more importantly in this another ethical change, we actually understood that if we treat the primary even in the static of metastatic disease, actually we improve patient survival. And this again, another great contribution by the STAMPEDE group which revolutionized the way we are treating prostate cancer. We are talking here about oligometastatic disease. So patients with few mets of course, but still treating the primary in this case with radiation therapy was able to improve patient outcomes in a significantly manner. And these now as being included in the guidelines, if you have a patient with oligometastatic disease upfront based on conventional imaging in this case we should go for radiation therapy to the primary, together with long-term ADT strength of recommendation strong.

What about surgery? Well, actually I have the honor to be here in 2006. And this our surgical mentor, actually, I don't know who knew this man, but actually was the most outstanding surgeon I have ever seen in my life. And actually in 2006 he had this idea of doing surgery for oligometastatic prostate cancer. And since then we have been doing that. That was 15 years ago and we actually treated the first one. And actually we say, "Well, are we ready for this? Is really supported, no data, only lab data, no STAMPEDE out there, nothing." Just an intuition from a great clinician. And we ask him, "So people will kill us?" "Yes, but remember if someone criticize what you do, that means that you're doing a good job." Actually, we kept on doing this. Everything was approved by our local ethical committee, but we are doing now surgery.

There is now actually a small phase two study which had the honor to publish [inaudible 00:16:32] oncology, as he is here with us, randomized patient to ADT versus surgery. Not STAMPEDE one, but like the STAMPEDE impose a phase three, but these are phase two. Surgery is anyway getting out of the tunnel. Let's put the link that way. And this another trial arm from the STAMPEDE, I think the Noel Clarke we talk about is try to assess the main question whether the surgery is as good as radiation therapy, whether we should eradiate the metastases that we see at conventional or functional imaging. There are still many unanswered questions. Last is metastatic castration resistant prostate cancer or actually no metastatic as well because in the last years we also seen a new, maybe artificial space of disease status, which is no metastatic castration resistant disease.

And we do actually available therapies in these disease setting, which is apalutamide, darolutamide, enzalutamide. We do actually have improved also the way we treat castration resistant disease even in the nonmetastatic setting. Well, one might argue that nonmetastatic castration resistant disease does not exist, is only a matter of imaging. If you don't see something it's because the imaging is not sensitive enough. And this has been explored also. And we are doing more and more PSMA PET in this specific space and we are sometimes trying to give indications for metastatic-directed therapy even in the castration resistant disease. But this is outside of any guidelines. There is no specific evidence. We are doing something, some treatments which are based on what we feel it's correct, but without any evidence. We should be very careful.

Despite these, another consensus meeting, and I had the honor to participate to these as well, showed that all the expert agreed in use PSMA PET, even in patient with CRPC, which is scary because the train again has left the station also in this specific disease setting. And when we talk about metastatic CRPC, what we have seen over the last years, a big revolution in this setting as well. 10 years ago, we talk about mainly ADT plus bicalutamide then you can remove bicalutamide, you do some anti-androgen withdrawal, which we don't know any longer. And then if they progress on ADT or docetaxel, actually you could give abiraterone or cabazitaxel. It was many chemotherapy for patients with CRPC 10 years ago. And now the revolution is here because look at how many drugs we have available for patients with CRPC. It's not only chemotherapy, is chemotherapy plus several other agents which have been shown all in phase three prospecting randomized trials to improve patient outcomes. And we're talking about patient survival.

Of course, the big issue is which drug for which patient or which treatment sequence. This is mainly an answer in many aspects. We have understood over the last years, for example, that we should not give two consecutive anti-androgen targeted agents, for example, that we should give chemotherapy instead of these in patients progressive after docetaxel. We have some new ideas on what to do, but still there are many data that we need to provide regarding the Optima treatment sequencing.

In conclusion, so there has been a huge revolution in prostate cancer over the last 10 years. It's really difficult to summarize all these infuse lights, but the main revolution was introduced by imaging. But imaging can lead to wrong decisions based on feelings rather than strong data based on prospecting randomized trials. And we have changed the way we are treating metastatic disease. The answer is clearly yes, we have many options available both in the castration sensitive and in the castration resistant disease phase. But we still need to address many additional questions and we hope this could be the basis of further collaboration for future studies. Thank you very much for your attention.