Alicia Morgans: Hi, I am thrilled to have here with me today at APCCC 2019, Dr. Nick James, who is a professor of clinical oncology at the University of Birmingham and Queen Elizabeth Hospital in Birmingham in the UK. Thank you so much for being here.

Nick James: Hi. Yeah, pleasure.

Alicia Morgans: Wonderful. So, I wanted to pick your brain a little bit about a really thought-provoking talk that you gave, actually earlier today at APCCC.

Nick James: Yeah.

Alicia Morgans: Thinking about systemic therapies for node-positive patients. So nonmetastatic, not M1, but node-positive patients, which is a sometimes overlooked population.

Nick James: It is. So, there were kind of three strands to my talk, so the first is what's the role of radiotherapy? And as you'll be aware, we just published data looking at radiotherapy in metastatic disease that showed that radiotherapy improves survival in low-volume metastatic disease. So, that's kind of to the right. And to the left, we've known for a while now that radiotherapy improves survival in node-negative, non-metastatic disease as well. So, my take on that is that if it improves survival both sides of this slice in the middle, it must improve survival in the middle. So, I would view radiotherapy as being a sort of bolted on component, so that was the first point I wanted to make.

And the second is, what systemic therapies do you give with it? So, again, I think it's pretty bolted down. You have to give ADT as part of that. But then the question arises, do you give ADT plus something else? And we've got data on that from within STAMPEDE, from two separate arms, one's docetaxel and the other is abiraterone. So in the context of docetaxel, the data when we last analyzed it in 2015 are relatively immature and we're looking to present updated data at ESMO, which we can maybe talk about another time. But the data that we have already presented is the abiraterone data. So just to remind people, STAMPEDE includes high-risk, nonmetastatic, so including node-positive as well as metastatic. The thing that links them is patients are all starting hormone therapy long-term for the first time.

So we presented an analysis at ESMO two years ago, which we're in the process of updating, that showed that for men with node-positive disease, there was a huge benefit from the addition of abiraterone just for two years. And what's more, when we looked at patients who got radiotherapy versus patients who didn't get radiotherapy, because it was a clinician choice at the point where we were recruiting, there appeared to be quite strong synergy between abiraterone and radiotherapy. So the patients who got both, the hazard ratio for gain over ADT alone was less than 0.2. So there was a bigger than 80% gain in failure-free survival and a slightly lower but still highly significant gain in metastasis-free survival. At the point we did the analysis, there were insufficient deaths to do a survival analysis, but we will do that next year.

Alicia Morgans: Wonderful.

Nick James: So it's obviously still preliminary data, but we've got other data coming up from STAMPEDE with abiraterone and enzalutamide in the same setting so we can do a pooled analysis with that. So we're pretty convinced that's going to come down to showing a survival advantage from just two years of therapy.

Alicia Morgans: And that's what I think is so impressive because I think the only data... So in surgical patients, for example, if they're node-positive, we have data from many, many years ago. There was an ECOG study that we all refer to as the Messing trial. So node-positive patients, only 96 people in the trial, but early ADT forever was superior to delayed ADT. Now this was an indefinite amount of therapy and actually very hard to implement because who wants to commit these patients who were surgical patients with just a node-positive, to indefinite ADT.

Nick James: Absolutely.

Alicia Morgans: But in STAMPEDE, you've included this population. You're now radiating the primary, which we do of course, but it's a defined period of time with this survival benefit attached, which is really, really useful to know.

Nick James: It is. And the other thing, which I didn't show in the presentation but I hinted at, is we've just done a health economic analysis on this. And it turns out to be very cost-effective within two years because it's a fixed price. You pay for fixed price, you get a huge reduction of relapse, which means you've got a huge saving down the line in not treating relapsed disease. And you've got around about a 50% reduction in symptomatic colloquial events, which is a-

Alicia Morgans: That's huge as well.

Nick James: ... big clinical gain and a big cost saving, so everybody wins basically.

Alicia Morgans: Absolutely.

Nick James: So it looks to us to be a very effective therapy. And what we're planning to do at the moment... Because abiraterone is on patent in the UK, it's hard to prescribe even inside the license because it's expensive in hormone-sensitive disease. But as soon as it comes off patent, NICE will probably be able to assess it as a, we hope as a clinical guideline, which is what they did with our docetaxel data. So they can make recommendations for use outside of the license then, which is what exactly what happened with docetaxel.

Alicia Morgans: Oh, that's exciting.

Nick James: So that's as part of our ongoing plans as to what to do with the data. We will update the follow-up and refer it back to NICE with a hope they'll do it as a clinical guideline.

Alicia Morgans: Absolutely. So I think really changing the trajectory for these patients because like you said, they've sort of been left out of many other things. So my hope is that you're able to get that guideline established. And I think that your quality data, that health economic analysis, should actually help with that a lot. And like you said before, and I think we've talked about before, it's really shifting the amount of time that people spend in these different clinical states and it's surprising how much money can actually be saved and certainly how much better the quality of life is when we ask the patients if they're spending less time in a metastatic state or in a relapsed state even.

Nick James: And indeed on the long treatment state. So one of the things that with hindsight, we half-assed within STAMPEDE is we sort of asked the duration question because when we put two years, well that rations the M0s, versus indefinite in the metastatic. The hazard ratios are the same or better in M0 than they are in M1. So it does imply that you don't need to get continuous therapy. So I think a separate thing we need to revisit in metastatic patients as well is this question of intermittent versus continuous therapy.

Alicia Morgans: Well, I hope you will because it's going to be challenging to get that through our American steering committees. And actually just had a conversation about that last night, the difficulty, because these things take time and they take patience, but STAMPEDE has shown us that it's absolutely possible in the UK to get both time and patience and to have such meaningful clinical outcomes. So I really appreciate you sharing this information about node positive patients. I look forward to the publication if it's not already out. And I appreciate your time.

Nick James: My pleasure. Thank you very much.