Scott Tyldesley: Thank you. Thanks for having me.
Leslie Ballas: You presented at GU ASCO, the 15-year update of the ASCENDE-RT trial. Fill us in on what we learned from this.
Scott Tyldesley: Yeah, so I'm presenting on behalf of the PI, Jim Morris, who couldn't come down, so I got the pleasure of presenting for him. And so ASCENDE'S been presented before at various different meetings, and this was really the long-term survival update with 15 year ... More than most patients had more than 15-year follow-up if they were still alive. So long-term endpoint on survival.
Leslie Ballas: And what did you find?
Scott Tyldesley: Yeah, so just a little bit of background on ASCENDE. So it's a randomized trial of dose escalation with external beam versus brachy therapy, and all the patients got pelvic radiation and a year of hormone therapy. And the initial report at 7 years and then the 10-year follow-up showed a significant difference in freedom from biochemical recurrence of almost 20% at 10 years. And at that time of the 10-year analysis, there weren't many prostate deaths. So at this analysis, we have more prostate deaths and we're updating on the overall survival. And the take-home point is there was no statistically significant difference in overall survival.
The point estimate was about 55% for the external beam and 60% with brachy, but not statistically significantly different. But it wasn't really powered for detecting a small survival difference. We can't see there's no survival difference, but it's not big. We're just under 400 patients in the trial to give you a sense of the sample size, and about half the patients have died at this point. The single most common cause of death was prostate cancer, but it was still only about 16% of the overall deaths or of the deaths where 16% were prostate cancer. There was a difference statistically in death from prostate cancer. The cumulative incidence of death from prostate cancer at 15 years was a little bit different, but an 8% difference, 8% versus 16% essentially.
It's a bit tricky because the patients were prospectively followed out to 10 years and we captured data like relapse and metastases and things, but after 10 years, it's mostly a registry updated event. So some of the deaths are, you know they died, but you're not 100% certain what they died of. So we did a secondary analysis where we included the unknown causes of death with prostate cancer to kind of do a sensitivity analysis around that. And when we included those deaths, which were a bit more common in the brachy therapy arm, the difference was a bit smaller. It was more like about a 5% absolute difference in cumulative incidence of death from prostate cancer. And the P value wasn't quite statistically significant. It was like 0.06 on the univariate analysis. So you could look at it and say, well, there may or may not be a difference in death from prostate cancer in this trial. And again, it's not really powered to show a small difference.
Leslie Ballas: You presented obviously the overall survival data. You did not include metastasis-free survival data at the 15 years. Does that have to do with the registry component beyond 10 years?
Scott Tyldesley: Yeah. It's because some of the patients obviously are still being followed in the clinic, but not on a study protocol where they're coming in and having forms filled out. So our ability to document metastasis uniformly between the arms didn't really occur beyond 10 years. But when we did the 10-year analysis, there was no difference in metastasis-free survival. There was a small numeric difference, but it wasn't statistically different.
Leslie Ballas: This always happens when you get long-term updates. You have to try to figure out how do you integrate the information from 15 years ago-
Scott Tyldesley: Right. A lot of updayes.
Leslie Ballas: ... onto our modern day, more recent trials. And another form of dose escalation is using a micro boost-
Scott Tyldesley: Right.
Leslie Ballas: ... as was done on the FLAME trial. How do you think about the use of a brachy boost versus a microboost given where we are today?
Scott Tyldesley: Yeah, I think that's an excellent point. And we know from FLAME and HYPO-FLAME and other trials that giving a microboost to some dominant intraepithelial lesion improves the biochemical disease-free survival as well. Maybe not the same magnitude as brachy. I think it's also true that the absolute difference in the dose or the biologically effective dose difference is smaller when you do a dill boost with external beam. It's a higher dose, but it's not as high as you'd get right around the HDR catheter or the seeds themselves. I think it's hard, and I mean, maybe it will one day be possible, but it's hard to imagine that you'll ever be able to give as big of a dose with something other than brachy therapy. And so I think that the difference between giving a FLAME type dose and the brachy dose, presumably the difference in biochemical disease-free survival will be smaller than it was with the technique we use now.
And maybe it'd be a 10% difference or 5% difference. And then knowing that even a 20% difference doesn't translate into a very big difference in long-term survival, you'd think, well, is it worth additional toxicity and cost of doing brachy therapy? And I think that's a good question. I think that we have to use this information to apply it to the patients in front of us. And for some patients who are quite young and are going to live a very long time and have good urinary function and you think you could do an implant without a lot of toxicity, I think it's probably still worth it for them. But for older patients who less likely to live 10 or 15 years, I think it's probably not worth the risk of going through brachy therapy. But I think it's an individualized decision we make with our patients each day like you do.
Leslie Ballas: Yeah. Really the question would be to draw on what you're saying is even though the dose, the biologic dose of that brachy therapy boost is higher than what you would give with a external beam microboost, do you think that that incremental dose difference matters?
Scott Tyldesley: I guess the short answer is I don't really know. I suspect it might matter for some patients and not for others.
Leslie Ballas: The ASCENDE-RT trial included intermediate-risk patients, I think about 30%.
Scott Tyldesley: That's right.
Leslie Ballas: Do you feel like those patients skew the results at all?
Scott Tyldesley: Well, we didn't present data on this today, but we did look in the past at those two subsets. As you can imagine, it's a small trial and it's small subsets. They were pre-planned strata that we looked at, and there's still a difference between brachy and non brachy. The boost with brachy is better in both intermediate and high risk. Obviously the event rates are higher in the high-risk patients, but the difference is a little bit smaller in the intermediate-risk patients. I think the other way it can affect the results is that if you're worrying about survival and death from prostate cancer, treating lower and lower risk patients isn't going to lead to a survival difference.
So it's really in those very high-risk patients that we might see a survival impact. So I think if I was going to design a trial to look at survival with a brachy therapy boost, I would probably be more selective than we were able to be in ASCENDE. It was also a kind of pragmatic trial because it was a relatively small province and it was mostly done in BC and a little bit in Ontario. It was hard to get, it took 10 years to get a sample size of 400 patients even. So to have done it in a thinner or smaller strata would have been challenging to do. But I think if we were going to do it as a big multicenter trial, that would be a good strategy.
Leslie Ballas: Thank you so much, Dr. Tyldesley.
Scott Tyldesley: No worries.
Leslie Ballas: Congratulations on your research.
Scott Tyldesley: Thanks so much. Enjoy chatting with you.