Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Nick James, who is a Professor of Clinical Oncology at the Institute of Cancer Research at Royal Marsden Hospital in London. Thank you so much for talking with me today.

Nick James: It's a pleasure.

Alicia Morgans: Wonderful. So I think that you again have stirred up a lot of controversies, some confusion, but also I think some clarity with the STAMPEDE trial. And I'd love to hear how you unpack all of the changes or the updates that we've had over the last few months, particularly around the high-volume/low-volume controversy in metastatic hormone-sensitive disease and then thinking about relapsed disease versus de novo metastatic disease and how all of this fits in with the CHAARTED data. So take it away.

Nick James: Yes. So lots of stuff. So I think for the AR targeting therapies of which we now have apalutamide, enzalutamide, abiraterone, it's very clear, there is no volume effect. They work across the whole spectrum. And so that's kind of ... Nobody debates that. So the debates with systemic therapies is with docetaxel driven by the apparent disparity between the CHAARTED and the STAMPEDE data.

Alicia Morgans: Yes.

Nick James: So in STAMPEDE, we've never been able to see a volume effect on any analyses we've done. But the thing we haven't done was to split the scans by the CHAARTED and also we did it by the last two criteria as well. So we pulled in as many of the scans as we could, which was about 80% of the scans, centrally reviewed them, classified all the patients retrospectively. And it's very clear that for the STAMPEDE population, which is 95% de novo, so very few relapsed metastatics, they're almost all de novo that there is no volume effect.

So the effect on failure-free survival, SREs, overall survival, is very consistent across the whole spectrum. So for us that puts all the systemic therapies in the same position for newly diagnosed metastatic hormone-sensitive disease, which is you can have a choice. You have a choice of chemotherapy or AR targeting therapy. Various reasons why you might want to pick one or the other.

Alicia Morgans: But not volume.

Nick James: But not volume.

Alicia Morgans: Yes.

Nick James: Where you have a choice with volume is in respect of treating the primary. So again, data we showed last year and published last year and which very rapidly has made it into pretty much everyone's guidelines was around treating the primary with radiotherapy. So we gave a near radical dose of radiotherapy to newly-diagnosed metastatics, classified them according to whether they were high or low volume by CHAARTED criteria. And essentially there was no effect really in the high-volume by CHAARTED criteria.

There was an effect in low-volume. There was a big impact on failure-free survival and an impact on overall survival of around 30%. So pretty much the same order of magnitude as abiraterone in our earlier trial and bigger than the docetaxel effect in absolute terms. Although obviously they're different trials, different times, and actually some of these patients also had docetaxel. So for volume now I think we've got very clear evidence from STAMPEDE, the HORAD trial, the meta-analysis [inaudible 00:02:57] that low-volume disease, you should treat the primary and that the evidence is with radiotherapy. There's no evidence with surgery.

Alicia Morgans: What do you say to those who had concerns about when that analysis was actually sort of redesigned? Because there's a lot of controversy around that and I think that you've had answers that actually satisfy me. But certainly, I'm one in, you know, many, many who treat this disease.

Nick James: Sure. Sure. So the controversy was that we didn't stratify by volume upfront. We decided after we'd started the trial, but before we did any analysis that this was likely to be important. So the stats analysis plan was updated prior to the HORAD data as well. We pulled in all the-

Alicia Morgans: That's important to say, I think.

Nick James: It is important. We pulled in all the scans, essentially reviewed them, we double reviewed a proportion of them as well. So we're happy that it's ... it was a pre-specified analysis and-

Alicia Morgans: With no investigation of the data prior to this-

Nick James: Prior to any analysis.

Alicia Morgans: Designation.

Nick James: Yeah. And then the key thing is that you then test for whether there's an interaction between volume and the outcome. And the key statistic here is that if it's less than 0.1, the test for interaction, then it's likely that you're looking at a genuinely different effect.

And the test was a lot less than 0.1. There was a couple of extra zeros in there. So there was very clearly a different effect and you can see it across all the different analyses. You can see it across the failure-free survival and the overall survival analysis and you see no difference in the high volume. So all the outcome measures lined up so we're happy it's robust. And actually most of the national, international guidelines seem happy as well because they changed almost instantly actually.

Alicia Morgans: I agree. You know one other question though that I have, and you've mentioned this, that some of the patients who are on that arm in the radiation analysis actually received docetaxel as well. In other parts of the world where there's easy access to things like abiraterone, there are many groups that are giving abiraterone plus radiation to the primary for these lower volume patients or certainly you could, particularly in de novo metastatic patients, consider docetaxel as was done in your trial. What do you think about this? Is there benefit to this triple therapy? And actually, I don't think your data can answer the question yet.

Nick James: It doesn't answer that question.

Alicia Morgans: So just your personal opinion, I guess, is what we're looking for.

Nick James: So we've got partial answers to that. So in respect to docetaxel, 18% had docetaxel. It was a stratification factor, because we made the change to the standard of care after we'd started recruitment when our own data came out. And the hazard ratios with and without docetaxel are the same. So it doesn't look like there's any reason to think that docetaxel and radiotherapy shouldn't be part of the standard of care, which is the view we've taken for our next arm, which is irradiating the oligomets.

Alicia Morgans: Yes.

Nick James: At ESMO this year we showed exploratory data on sites and distribution of metastases. So one of the things in the CHAARTED criteria, and it's a sort of super small point, is that one of the mets has to be non-midline. So you can have a hundred mets if they're all midline, you're low volume in CHAARTED, which we clearly showed in our exploratory analysis was nonsense. It didn't matter where the mets were, four or five was the magic number. So for our next round of trials, we'll set the cut points at four mets, irrespective laterality basically.

Alicia Morgans: Okay.

Nick James: And bone mets. In respect of abiraterone, what we know from the prior abiraterone data, where the M0 patients got radiotherapy was there was a very strong interaction between radiotherapy and abiraterone that looked synergistic, i.e. you've got a bigger effect with the two than you've got with either on their own.

Alicia Morgans: Yes.

Nick James: So there's no reason to think that adding abiraterone with low volume patients wouldn't be a good thing to do on the basis of our own M0 data, but there's no data in M1. The PEACE-1 trial will give us that data, but that's still another year or so from reporting.

Alicia Morgans: Yes. Well, as we wrap things up, I'd love to hear about what is on the horizon for STAMPEDE. You mentioned the oligometastatic trial, but in addition to that, you have some health economics and you also have some quality of life data that I think many of us are really looking forward to hearing about.

Nick James: Yes. Well of course, as you know, you're collaborating with us on the analysis of the quality of life data. The really interesting stuff is that we've got around 600 men who overlap between the docetaxel and the abiraterone arms, they recruit simultaneously and we have comparative, therefore, quality of life data on these two which will be the only comparative quality of life data for two different additional therapies in the hormone-sensitive setting.

So we've submitted that as a late-breaking abstract. We haven't done the analysis yet so I don't know what it shows. We have also done the health economic analysis, so this will be using UK national health service prices, so obviously different from elsewhere, but nonetheless will be very important and in particular we'll be able to show the M0 data for abiraterone, which is likely to be very interesting once the price drops to generic and people start worrying about where you prescribe it.

Alicia Morgans: Absolutely. Well, I sincerely thank you for updating us again on all of the disruption, the lovely disruption that the STAMPEDE data inserts into our practices. And I look forward to talking to you again and hearing more updates at GU ASCO. Thank you so much.

Nick James: For sure. Thank you very much.