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Karim Fizazi: Thank you Tia, and first I would like to thank Silke and Aurelius for inviting me today. So I need to, I guess to critically review the three talks you've just heard regarding a very special situation, which is that of clinical positive lymph nodes in prostate cancer.

So my disclosures and why you're seeing them. I would like also to thank Dr. Roach and Dr. Murphy for sending me their slides on time. I would like also to remind Dr. James that when he has a discussant he should send the slides before the meeting, not after the meeting. Thank you, Nick. No, he sent me yesterday night.

Anyway, so we love level one evidence and I think level one evidence remains really, really important in medicine. So what do we have for prostate cancer?

So first in localized disease, we have actually around a hundred randomized trials asking various questions. I was really astonished when [(1:05) inaudible did the ICECAP,] realizing how many randomized trials we're able to do. It's huge.

Now, for metastatic disease, it's also quite many, especially in the last years. We saw many, just in last year we saw three new randomized trials. This is really nice. Now what about this very special situation which is that of clinical positive lymph nodes, such as the gentleman, and this is really key because those patients are potentially curable, but obviously they have a high risk of dying from the disease.

Well basically, we have nothing all more or I cannot mention only one randomized trial specifically focusing on people with not all disease based on imaging. We have that based on pathology but not on imaging. Actually, we should do a better job in the future. I think this is really important for these men.

So, radiation therapy for cN1 disease, should we use it? Yes or no? Mack showed us two very important trials. One from the Nordics. We have one from Canada and others that established very clearly that we should use a local treatment in men with high-risk localized disease, very important data. But actually it doesn't apply directly to patients with N1 disease because these patients were not included in these two trials. They were out, it was an exclusion criteria as I can tell. So it's just indirect analyses that we can get from that.

Now, we get non-randomized data from STAMPEDE for patients with cN1 cancers. And actually we looked at relapse for survival, based on PSA rises mostly by radiation therapy used. And what they were able to report, Nick reported that some years ago, was that there was suggestion that patients receiving radiation do better as compared to patients who do not receive radiation. Having said that, of course it's not a randomized part of STAMPEDE. We need to be cautious, and actually when you go to the details, patients who were not planned to receive radiation had a much higher PSA as compared to those who were planned to receive radiation. And they are biased, we all know those things.

This is also true and even more true for the analysis of the US National database regarding this question of local treatments. Of course, you might see, well it's about 3,000 men, so it's huge. Fantastic. And when you see the curves, it seems to be very clear that you should give a local treatment to those men. But, if you go again to the details, patients in the control arm were older, were actually secretly had more comorbidities, they had worse insurance coverage, and they have worse cancers based on Gleason score or our PSA. Huge bias, obviously. So how can we trust this data? Even if you do a multivariate analysis, you're never sure. Nothing can really replace a randomized trial. So we need to be cautious. I still believe that it's true, but it's a belief, we need to be very cautious about it.

Now, probably more important to vest data of cN1 disease is the direct analysis and direct from the musician of radiation therapy in STAMPEDE for patients with oligometastatic disease. It's not exactly all current situation for this session, but it just worse, let's say. So it's, we're talking about a man with either lymph nodes in the retroperitoneum, not in the pelvis, only, or patients with a couple of bone mets. Here, we do see benefit not only for progression for survival, but also by overall survival when radiation therapy is used. So in other words, we have level one evidence for high risk localized disease. We have level one evidence for oligometastatic disease. We're just in between here for ([5:18) inaudible]. It implies basically that radiation works for these men, but even if we don't have direct comparison, and this is basically what was said in a recent review with a beautiful editorial from two famous people like Dr. Gillessen, Dr. Tombal.

So what about the field? Again, we have data, randomized data regarding the field of radiation, the RTOG 9413 trial that was mentioned by Dr. Roach, but again, those patients had not all, zero disease. So we are not sure that larger field is actually better if have an N1 disease.

What about lymphadenectomy? The data is also weak. The paper that was shown about Dr. Murphy's just based on 51 men with clinical and positive disease. So, of course we think that surgery might help some of these men at least, but it's really weak evidence that we have at the moment.

What about drugs? So for the sake of time, I don't want to hear the bell, I'm not going into too much detail for docetaxel and Nick already explained the current situation, but just to make it short, probably 10 or 15 years after the last patient was enrolled in the randomized trials that treated for high risk localized disease, we still don't know for sure whether we should use docetaxel as standard treatment for this man. This is because even if progression for survival or relapse for survival, based on PSA is clearly improved, we don't have more meaningful endpoints demonstrated overall survival metastasis for survival. Last year, we had clinical relapse for survival in genetic 12, but still it's difficult to make it yes, or no, or standard, and this is based on opinions.

What about abiraterone? I think this is one of the beautiful pieces of work that was done in STAMPEDE. Maybe even the best piece from STAMPEDE. Abiraterone was randomly tested in STAMPEDE in high risk localized disease and also in a set of patients with not all disease, almost 400 men. Patients were randomized on a one to one basis and as shown by Nick. The difference in outcomes based on PSR relapse mostly, is just big for patients who are very likely to relapse. As you can tell, patients on ADT alone, after three or four years had already relapsed for half of them. Now for patients receiving just two years of abiraterone, again four years afterwards, less than 20% of them have relapsed. So we eventually translate into more clinically meaningful outcomes. Of course, it will become a standard for these men.

Now just a few comments about the anatomy and the imaging. We're separating historically pelvic lymph nodes versus retroperitoneal lymph nodes. We say this one is potentially curable, so it's localized if you will. We have one is metastatic disease. Is it really true? I really wonder, to be honest. And I wonder whether we should revisit this concept and for also the sake of doing trials. Maybe pull them together, I think something about that.

Now what about imaging before PSMA PET is coming and we see much more notes, and we have probably zero evidence regarding treatment of PSMA detector notes at the moment. Not even talking about randomized trials.

We will have a randomized trial. Oh finally. So we will have a randomized trial and I'm really glad that we have it, but again, it will tell us whether PSMA PET should replace conventionally imaging. It will not tell us how to treat this man, and this is important and we should do trials to address those questions.

So in conclusion, insufficient level of evidence, we need randomized trials regarding the current treatment. Personal opinion here, some recommendation ADT, likely yes. Again, no randomized trials for cN1 disease, but it's very likely optimal duration. I don't know whether that should be two years, four years, lifelong. Who knows? So probably we need to discuss on on a case by case basis. Local treatment of a primary, I think yes, we can say based on STAMPEDE data, based on the localized Harris Data from the Nordics and Canada, we're just in between. Yes, we should probably give a local treatment to these men. Local treatments of the nodes, likely yes, but again, still struggling with the data. Large fields of radiations, large or extended lymph node dissection, likely better, but we are not sure to be honest.

Drugs, abiraterone definitely, if STAMPEDE relapse for survival translates into metastasis for survival or even overall survival in the near future then I think it will become a standard of care for these men. Docetaxel, still struggling with the data, we will learn more probably in just a month from now at ESMO. Thank you very much for your care and attention.