Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, a friend and colleague, Dr. Nick James, who is a Professor of Prostate Cancer and Bladder Cancer Research at the Institute of Cancer Research at the Royal Marsden, in London, in England. Thank you so much for being here with us today.

Nicholas James:  A pleasure as always.

Alicia Morgans:  Wonderful. Well, Nick, you gave a fantastic presentation at ESMO 2020, giving us an update on the STAMPEDE data as it relates to the abiraterone arm. And I would love to hear your take on some updates from that study.

Nicholas James:  Thank you. So when we presented abiraterone data in 2017, we had relatively immature follow-ups simply because the difference was so big. We didn't need to run the trial for any longer to get statistical significance. So we had around 200 deaths on the control arm, at that point. We got over 300 now, so more than 50% more events. So we reran the analysis just for the metastatic patients on this occasion. We're separately going to do the M0 patients at a later date, and we'll pool them with the abiraterone enzalutamide arm. Because we think by pooling those two arms, we have the potential to nail a survival advantage in M0 patients, which nobody else will have, I don't think. So that data wasn't included this time. I guess the key thing about this, we've got around a thousand patients, so one of the things that were very interesting was how many of them were still on treatment.

So 500 randomized to abiraterone and around a quarter of those are still on treatment. So the minimum follow-up now, so we finished recruiting around 2014. Yes, January 2014. So the minimum follow-up on this is now six years, more than six years actually. So we've got looking at a very long duration. So one of the things we will come back to it, which we didn't analyze this time, is things like late bone morbidity, late cardiovascular events because we are concerned that they might actually be over-treating some of these men. The outcomes are so good, we might have been better off limiting the duration of exposure, essentially. That's also a question for another day, but the most important point is that the hazard ratio for the metastatic population is pretty much identical to the hazard ratio, as it was back in 2017.

So let me just look at that. So it was 0.61 in 2017, it's 0.60 now. So very stable also very important things, we updated our docetaxel long-term followup at ESMO last year. And what we saw was that the hazard ratio with longer followup is not proportional across the duration of followup. As to say the curves gradually came together around six or seven years. It didn't actually cross, but the gap was much smaller. That doesn't happen with the abiraterone patients as we get to longer follow-up. And I don't think any of the other trials have got such long follow-up. LATITUDE maybe has, but they've only got high-risk patients, but the other AR targeting agents have not. So we think that's very important because whilst early on the dosing and the abbey curves run together. We haven't run the head-to-head comparison again, but it's likely that they will not run together once you get further out, which is potentially very important for funders and policymakers and stuff.

The second thing that we did was look at the high risk, low risk split because LATITUDE obviously only had high-risk patients. That was their target population. That's about half of our population. And what we saw was that the hazard ratios were nearly identical in the two groups. So there's nothing to suggest and you wouldn't have expected that abiraterone wouldn't work in low-risk patients. The benefit is the same. In fact, the absolute benefit is bigger because obviously if you've got a better control arm survival, you improve it by the same proportion, you get a bigger, absolute gain. So we think that's very important for funders.

The third thing is we have median survival estimates now for the abiraterone arm, as well as the control arm, which we didn't have before. So the median survival gain is just under three years. So it goes up from 3.8 years to 6.6 years. You don't see a massive gain. And if we go look at failure-free survival, the Delta on that is a bit over three years. So it's 0.96, just under a year. It goes up to 4.3 years, the median time to failure. Because one of the debates that we had back in 2017 was could you have salvaged these men by crossover? And the answer is, you couldn't have really,  because you've got about six months to catch up from treatment using CRPC to try to catch up a 3.3-year headstart in the abiraterone arm. So whatever the salvage treatment you give, it's not feasible that you could have caught up, I think. All of the other secondary endpoints, failure-free survival, skeletal rated events, they remain very stable. So for example, skeletal events, which I think are particularly important, the hazard ratio is 0.56. So you've got a 44% improvement reduction in the skeletal events.

So all in all the results are very pleasing. The benefit is stable. It's maintained out to six or seven years. We're not seeing any significant toxicity issues. The rates of toxicity at four years are the same between the experiment arm and the control arm. This, of course, far more patients on the experimental arm at risk at four years, but there are no differences in the rates of grade three, four toxicity. So it's very reassuring data. And also I think reinforces the fact that it shouldn't just be high-risk LATITUDE population, it should be available for the whole population.

Alicia Morgans:  Absolutely. And it's interesting. I mean, there's just so many things to unpack here. One of the things that you mentioned just in terms of survivorship and bone health and these skeletal events, it's very reassuring I think that we see that despite the steroid exposure in patients on abiraterone, they're actually not experiencing more fractures because we're controlling the disease essentially. And that's so important as we continue to understand the importance of bone health. And we don't actually have a great treatment except for patients who overtly have osteoporosis, for example, to use bisphosphonates or denosumab in that hormone-sensitive setting. It's just not done based on multiple trials that have not shown a clear benefit in that population. So it's really important and exciting that this is a method to prevent those events. And as you said, other complications are things that you will be looking at in the future.

Nicholas James:  So relating to bone health, we looked at zoledronic acid in one of the early arms of STAMPEDE, and it doesn't affect overall survival. It doesn't affect failure-free survival as a cancer treatment. But if you're looking at say eight, nine, 10 years in the lower-risk patients, exposure to ADT abiraterone, we have progression.  There's got to be an effect on bone health, osteoporosis, and so on. So I think increasingly for these men we should be looking at whether they should be on osteoporosis doses of bisphosphonates or denosumab, whatever that you pick. And I think what our experience has been that the bone mass will actually heal up completely with long exposures to abiraterone. So it's perfectly possible to go measure there, do a DEXA scan, measure their bone density. And I think that should be factored into people's thinking now. So we've got an MD student, a doctoral student, looking at bone fractures in men who have not got disease progression specifically to see if we can measure the magnitude of the effect or not. They may not be in effect, but it's likely they will be.

Alicia Morgans:  And that's phenomenal that you're taking the time to do that, because as you said, even if we're not doing it monthly for SRE's, although sometimes I see that in practice, we really need to pay attention to getting those DEXA scans, understanding bone mineral density, and for patients with advanced osteopenia osteoporosis there absolutely is an indication to prevent fragility fracture. So I really do look forward to seeing the work that comes out of this. It's just the gift that keeps on giving, STAMPEDE. So wonderful. So I think as you think about this overall, and you think about the quality of life data that I know you and the team with Dr. Rush had presented and talked about, and thank you for including me in that, it's been quite an honor and a pleasure. What are your thoughts on this chemo hormonal versus abiraterone approach in a world in which you were not restricted? Because we know that in the UK, there are some restrictions or have been in pre-COVID times.

Nicholas James:  There are, that's right. Thank you very much for helping us with this, it actually has been a bit of a fruitful collaboration. So I've changed my thinking about this. I was previously thinking, well, it's only a 16 week hit from cycle one to cycle six or whatever it is, 18 weeks from beginning to end, you just stuck that up, and then you're fine, your quality of life is back to normal. But as you know, the quality of life data that you helped us analyze shows that there's a year, you've still got a deficit in the quality of life with docetaxel compared to abiraterone or indeed compared to ADT alone.

So I find this data really quite compelling. So I now think that you should only really be using docetaxel in people where you've got no other options and your healthcare system won't buy abiraterone. But as abiraterone comes off patent, abiraterone probably becomes cheaper than docetaxel as well. So I think I strongly now lean towards abiraterone as being the better treatment option. To mention on that actually is, we and others are looking obviously to see whether there are biomarkers that might say, well, this patient actually is going to be resistant to abiraterone and, or sensitive to chemo or vice versa. So that may change my mind again. I mean, maybe we will be able to partition the population up by some biomarker, but at present, we can't.

Alicia Morgans:  And I think that that's great. I know that work is happening in CHAARTED. Is that work also happening within the STAMPEDE population?

Nicholas James:  So we've got around 5,000 sets of tissue blocks pooled in now that could get [inaudible]. So we are analyzing these multiple ways. We're looking at expression profiling from the RNA. We're looking at the various immunohistochemical analysis. We're looking at, we haven't done much yet, but we will be doing DNA mutation analysis, both in the tumor. And we've got germline samples for most of these patients. We've also now got this huge image bank that Noel Clarke is looking after at the [inaudible], with I don't know, I lose track of how many thousands, but many, many thousands of sets of baseline images. So we've been doing a whole load of analysis around tumor burden in relation to response to abiraterone and response to Docetaxel and so on, and the radiotherapy to the primary data. So we've got a whole load of stuff coming out from that.

Alicia Morgans:  Wonderful. Well with each presentation, I feel like I always have a million more questions, but I'm really excited to hear this longer-term data, even with patients 25% of them still on at this six-year, follow-up approximately and reported one patient still on at eight years or so. So this is really compelling data, really exciting, and I think we're all very excited. But if you had to sum it up, what would your message be to listeners?

Nicholas James:  Well, I think you've summed it up nicely. I mean, basically, the benefit of abiraterone remains substantial. We're looking at more than a three year gain in median survival for the whole metastatic population. These are big gains. I'm not sure I've come across a bigger gain in any trial than in adults with a solid tumor. And as abiraterone comes off patent worldwide, it's a very affordable gain as well.

Alicia Morgans:  Well, I hope that we all ultimately have good access to abiraterone in this setting over time. I commend you for the work you've done with STAMPEDE. I also commend you of course, for the work that you've done in getting abiraterone for patients in the UK, given COVID. And I really do look forward to continuing to work with you and continuing to learn from STAMPEDE.

Nicholas James:  Thank you very much.  Thank you for the opportunity to talk.

Alicia Morgans:  Thank you.