Matthew Smith: Next two presentations sort of point, counterpoint. Karim Fizazi is going to defend the position to treat such patients as low volume mHSPC. Karim?

Karim Fizazi: Thank you, Matt, and good afternoon everybody. Big thank you, obviously to [inaudible] for not only for inviting me, but for making this Congress so unique and so great. Very well done.

So, my disclosures first. Participation to ad boards and talks. And I think we have one and actually potentially two issues with that question. The first one is that, in contrast to most, if not all cancers, we tend to treat patients with metastatic cancers and sensitive disease, according to what we call disease volume, which is not necessarily a very nice word, but metastatic burden. I guess we have some reasons to do so, reasonable reasons. For example, we have quite robust evidence from STAMPEDE for selecting prostatectomy directed to the primary only for men with oligometastatic disease, because there is evidence for survival for these men, but not for those men with multiple metastases.

Having said that we don't really know whether using radiation therapy in men with more extensive disease may prevent local symptoms when patients develop CRPC. Regarding systemic treatments for second generation, AR axis inhibitors, Abiraterone, [inaudible], obviously, those drugs work regardless of tumor burden. And this is very clear, I think we have now eight phase three trials, super consistent. For Docetaxel, this is more debated. Those are subgroup analyses from phase three trials, STAMPEDE supporting a similar effect, whatever the number of metastasis while CHAARTED reported novel survival benefit only for men with multiple metastases. But actually things are more complex. You saw already these slides and I would like to thank Gwenaelle Gavis and Edoardo Franchini, but also Chris for providing this data, because I think it's important. Not only we need to count the metastases, if you want to figure out about the prognosis, but also to consider whether the patient has a novel metastatic disease or a relapse.

I'm saying that because as you see, there is an outlier, and the outlier with a better prognosis is a man with a relapse from localized disease and only oligometastasis. And these men actually live approximately eight years and actually perhaps even better now or longer now, thank to all the treatments that were invented in the last decade. Having said that, the three other groups, so in other words, all the novel men, oligo and multiple metastasis, low volume, high volume, and also patients relapsing with multiple metastases, don't do well. So I think this has important consequences. For example, coming back to the Docetaxel story, actually STAMPEDE only included the novel patients, and this is probably why we see a consistent effect of Docetaxel in low volume and high volume men, why CHAARTED with enriched in patients with relapse with oligo metastases disease and these men live better, maybe they don't need those Docetaxel treatment.

Second consequences, we will speak about deescalation strategies and also intensification strategies. I think that deescalation strategies is very reasonable thing to consider in men with oligo metastatic and a relapse because they live long anyway, but for all other subgroups, I still think that we should go for mostly intensification strategies because [inaudible], the second issue obviously is about next generation imaging. So Mike really very nicely set the scene. We now have access to these new fancy imaging. More lesions are often seen, often we perform a pro, so we don't even have bone scan, CT scan issue. All of the label evidence from phase three comes from conventional imaging.

So, if you are facing a man with low burden by conventional and high burden by next generation imaging, what should you do? Radiation therapy to the prostate, second generation AR targeting, Docetaxel, triple systemic therapy, metastasis-directed therapy. Well, we don't have evidence or strong evidence, no phase three, for sure. But I think addressing all these questions one by one, sorry for that. We should just think about the patient and try to make sure that what the patients will benefit from and that adopt actually should benefit to the patient. Let me try to take them one by one. Prostate radiation therapy invest scenario. We do have evidence from STAMPEDE based on conventional imaging. Again, nothing with new generation imaging, but I think practically speaking, if you are invest scenario, my answer is a yes answer. We should use radiation therapy, even if a PSMA shows multiple metastasis.

Number one reason overview overall survival benefit seen in STAMPEDE still may apply to [inaudible]. We don't know. And if, if so, we don't want to deny all the patients from this benefit. Number two, there is a possible better local control. Even if there might be no OS benefit, number three, the modern radiation therapies associated in my experience. And I'm not a radiation therapist with modest additional toxicity and in my country to be harnessed modest cost as well. So lots of good reason to recommend prostate tradition therapy in the situation. Second AR axis inhibitors. Big yes. The evidence is super big. Multiple metastasis OS is demonstrated low volume. Same, I think we should really make this a standard of care for these men. The big question is the optimal duration, do men with low volume disease needs really until CRPC onset treatment. I really don't know. Maybe two years is sufficient.

I have no clue, but really we should use these agents. Docetaxel, as I said for these man loud volume by conventional imaging and potentially high burden by next generation. I think the jury is out and we have pros and cons from STAMPEDE and from CHAARTED. So we may debate forever, but whatever, what you think about that, we should not use Docetaxel alone if we decide to use Docetaxel. So to me, it's a no for Docetaxel alone. For triplet, the data are just arriving right now. We have clear demonstration that low graphic progressions for survival is improved significantly in low volume man, when using three systemic agents compared to two from piece one, we are waiting for, similar analysis in [inaudible], at least four OS. We don't have RPF analysis in RAs and enzyme at hopefully we will soon be analyzed and updated.

So we will, I think we will soon have a clearer idea about this question. And OS is a major in piece one at least. And I suspect that this is also the case in the RA sense. So I guess practically speaking, I should say to be considered on a one by one basis in a young man should not really know for sure whether it's two to four burn metastasis, because you may debate whether a big lesion is actually emerging from two et cetera. And finally metastasis is directed therapy, we don't have evidence. We need trials. Good news trials are coming and with us, I think the big thing now is to forget about counting metastasis and support biology studies so that we can have biomarker stratification super soon. Thank you very much.