Noel Clarke: Well, this is a humble interpretation of some data from STAMPEDE and others. Thank you, Matt, for that, and good morning everybody. I'm going to talk about the optimal treatment of newly diagnosed metastatic prostate cancer, building on some of the information that we've just seen. We've been lucky. We've had a lot of large volume papers which have helped us understand the disease process rather better. Yesterday there was a statement that how do you prove that treatment doesn't work and that is to plan a trial which is too small. I'm pleased to say that all these trials are big enough so that we can unpick them. I'm going to look at this building on the thoughtful presentations from Thomas Steuber and others about local and systemic therapy, the volume risk and the benefit from treatment.

Now, we've been lucky with the STAMPEDE trial. We've got two translational groups set alongside working and embedded within the study, the Biomedical Imaging Group, which is based in Manchester, and the Biomedical Research Group, which Gert coordinates down in London. We've been collecting the various images from the STAMPEDE trial. We currently have about 5,000 scans centralized, looking at treatment response, and our aim is to get all of the trial scans in so that we can unpick some of the outcomes in relation to treatment. When you've got a big trial like this and you can centralize data and ally it to outcome, you can do a volume risk console diagram analysis like this. You can see the sort of process that we go through. For M1 we had just over 1200 patients divided up into the arms and you can see how it concentrates down to the number that you have to enable to do various analyses based on current thinking. 

The image analysis comes in, we categorize it for non-regional lymph node metastasis, visceral metastasis and so on. We can correlate that with defined outcome measures that we have, overall survival, failure-free, skeletal events, et cetera. 

Now, the first bit I'm going to tease out is this, the management of low volume metastatic disease. What the data has enabled us to find is that there is, in fact, a threshold effect for primary treatment using radiotherapy, of course, we didn't use surgery in STAMPEDE. That was published in this paper, which you've seen already very clearly. Again, this illustrates the importance of having a big enough trial. I think in renal, I don't think the trials are big enough to make any definitive comment. We can see that below a certain metastatic burden, I'll come back to that title, then we do have a definite benefit. Very clearly, you can see on this pre-specified subgroup analysis by metastatic burden, looking at the interactions, that these populations are clearly very different. 

Rob showed this a slide earlier on. This is that there is a threshold effect for disease burden, which is picked out by a standard bone scan. We don't quite understand why, but it is true. It's a predictive factor. We've gone on, I'm not going to show you this data, but we've gone on and measured the actual volume using bone scan indices. That actually plays out, that the volume of disease as shown by the bone scan is actually predictive, one of the very few predictive markers we have of outcome in prostate cancer.

Our conclusions from this bit of work are that low disease burden, there is a volume threshold effect whereby treatment of the primary with radiotherapy is beneficial. It remains to be determined whether surgery has that effect. We don't know. This threshold is predicted by the conventional bone scan, no matter what other scans show. If you have that threshold, you do get the effect. 

Now let me come to systemic therapy, the volume, risk, and benefit, because there's very confused thinking in volume and risk definitions. You can see in this table very briefly that this sets out all the different volume and risks definitions. They are different, none are validated, and there are common themes. None actually pays any attention at all to what the lymph node burden is. We know that about 15% are M1As. In other words, they have lymph node only disease, a different biology. 

Let me come to this, which has just been published, the role of abiraterone and ADT in high and low-risk metastatic hormone naïve prostate cancer. We've got two papers, large volume trials, one LATITUDE, and one STAMPEDE. LATITUDE obviously had a risk categorization in it. I'll bring you back to the consult diagram, which this is the work of Alex Hall and Adnan Ali in Manchester. Again, we've pulled in all the scans, 990 M1 patients, standard of care just under 500, standard of care in Abiraterone about the same number, and that boils down to about roughly 450 in each that have got evaluable scans. 

Now the first thing that we noticed was that when we applied LATITUDE low and high and CHAARTED low and high criteria to the STAMPEDE trial, we had a very high proportion of patients who were classified as low CHAARTED or low LATITUDE, about 44% in CHAARTED criteria, about 47% in LATITUDE. That's a lot of patients actually who are not eligible for treatment using current criteria. When we look at the LATITUDE risk stratification, this is what we find, overall survival, failure free, skeletal events, progression-free, prostate cancer-specific death, absolutely no difference. If you have the disease, you get the benefit from Abiraterone. When we look at the interaction value by metastatic volume, there's a homogeneity within this population. It clearly works as a systemic treatment. When we look at the same population and apply CHAARTED criteria, we get exactly the same effect, overall survival down to prostate cancer-specific death. You can see from the forest, there is really no difference at all, and the interaction by metastatic volume is exactly the same. 

Let me come to this, the CHAARTED and STAMPEDE issue, which Chris has talked about because this is really a difference. CHAARTED obviously had a low volume effect. GETUG-15 in both its analyses showed the same, but in STAMPEDE we have had uniformity across the piece. This is Gwenaelle Gravis' analysis in European Urology 2018, looking at the distribution of high and low volume patients in CHAARTED. She did the same for GETUG-15. The graph looks very similar. The numbers are smaller. You look at this, this is the low volume population. What you can see, as Chris very honestly said earlier, is that a very large number of these patients have had prior local therapy. We know that the biology is very different. 

I'm just going to show you in a brief snapshot of the ESMO 2019 Late Breaking Abstract 8440. We are embargoed so I can't show you much of this, but I can show you what's in the abstract. This is the longterm followup for docetaxel for hormone naïve prostate cancer patients. This is de novo, remember, the majority anyway, and the subgroup analysis for metastatic burden. We had the cohort selection here, again, the consort diagram for M1 patients, nearly 1100 patients. Arm A, 724, that standard of care ADT, and arm C, which was simply docetaxel. We excluded the zoledronic acid cases. We looked at them in relation to CHAARTED low and high. The median follow-up for the M1 cohort was 78 months with a median follow-up of the burden cohort of 72 months, so long enough follow-up to get a meaningful difference. This is what we found: for low-high burden, burden cohort, M1 cohort, no difference. 

What we can say with some degree of assurance is that in de novo metastatic disease, for those patients receiving standard of care ADT plus docetaxel, there is an effect, whether there is low burden or high burden. Indeed, the effect in the low burden patients seem to be greater than that in the high burden patients. My final conclusion in relation to this, there is no dichotomized volume burden related effect relating to docetaxel, and the prostate cancer patients presenting with de novo M1 hormone naïve prostate cancer should all be considered for combined systemic treatment with docetaxel or novel ADT combined with standard ADT if they're fit. Thank you.