James Yu: Dr. Ballas, it's a delight for me to be here talking with you virtually. So this is a study that is many years in the making that we presented at ASTRO a couple weeks ago. And the portion I'm going to discuss is the quality of life results from the randomized phase III trial of SBRT versus hypofractionated IMRT for localized intermediate risk prostate cancer. The study numbered NRG-GU005. And these are our disclosures of the folks involved in this abstract. So if you recall the study rationale, you have to remember a time before SBRT was so popular and so maybe 10 years ago, moderate hypofractionation was the real standard of care for intermediate risk prostate cancer. And at that time there were a lot of people doing SBRT for prostate cancer, but there were a lot of skeptics as well. And so we decided to mount a randomized controlled study comparing moderate hypofractionation to SBRT.
And kind of unusual for this, we decided to go with superiority design because there were some data from Skyler Johnson that SBRT may have an improved outcome in terms of patient reported quality of life, particularly at two years in the bowel and urinary irritated and obstructive domains. As well, given speculation about the radiobiology of SBRT, we hypothesized that there may be a benefit in terms of disease control that I think has been discussed between you and Dr. Ellis. And those primary results unfortunately, in terms of disease control were technically negative. We were going for superiority, we failed, so it was deemed to be futile. But these are the arms between the study IMRT and SBRT. You can see IMRT included 70 gray in 28 fractions, and then later in the course of the study we also included 60 in 20. So the two most popular hypofractionations. In the SBRT arm, we went with what was standard at the time, which was 7.25 times five.
And you can see also that the margins of treatment are a little bit different, a little less generous for SBRT. Again, one of the things to note about our study was that the maximum dose to the PTV without urethral visualization is 38.78 gray, which I think most of us today would say is a little on the cool side. In contrast to PACE-B, where you're trying to get the prostate CTV up over 40 gray. These were the patient characteristics, they were very well-balanced between the two arms. And you'll also note that we stratified by rectal manipulation, particularly SpaceOARs. So these were intentionally stratified and intentionally balanced between the two arms. We randomized almost 700 patients, so our statistical plan was a little bit unique also at the time. So rather than looking at the mean cohort wide patient reported outcomes measures, we wanted to look at individual patients and the frequency at which patients experience what's called a minimally clinically important difference.
So if a patient went compared to baseline down in quality of life in one of the five domains, we flag that as a MCID and we did that at one year and then at two years post-treatment. So I think our kind of methodology is a little more sensitive to individual patient experience as opposed to everything kind of getting glommed all together into a cohort mean. And we also performed exploratory longitudinal analysis of that cohort mean as well, but that was exploratory. So these are the results. So compliance was excellent. You typically don't see numbers in 80% and plus in terms of compliance to the EPIC-26 survey. So we were very happy about that.
And also we noted that the baseline score, so pretreatment, in the five domains were balanced between the two arms, so that was good as well. What we found was one year after radiation that fewer SBRT patients experienced an MCID in the sexual domain and fewer patients in the SBRT arm experienced a decline in the bowel domain. And then if you further follow that out to two years, the primary endpoint of bowel domain MCID at two years was met favoring SBRT, which is what we predicted. As well in the urinary incontinence domain, it also favored SBRT.
So in that longitudinal model of the cohort means, we also found that indeed treatment arm favored SBRT in the baseline EPIC urinary incontinence and as well in the bowel domain, which is what Rod Ellis presented because that was a primary endpoint. If you look at traditional measures of toxicity, these are investigator initiated toxicities. You'll see that actually both treatments were very well tolerated with grade three toxicities only being about 2.5% GU for IMRT and 0.6% for SBRT. Very little rectal hemorrhage about 1.5 versus 0.6%. If you look at grade one, grade two, that's where things become significant in terms of comparisons between IMRT and SBRT. As well fatigue, there's a little bit more fatigue in the IMRT arm. So our key findings, fewer patients who underwent SBRT had experienced an MCID and sexual and bowel health related quality of life at one year, and urinary incontinence and bowel health related quality of life at two years. Longitudinal analysis also favored SBRT in terms of urinary incontinence and bowel. And SBRT is very safe for the treatment of intermediate risk prostate and associated with low rates of investigator reported toxicity.
Just to put this in context with PACE-B, so you can see that we mirror the bowel differences, right? PACE-B also found that bowel related side effects are lower. We did kind of reverse the urinary incontinence, which is interesting, I think. As you recall, PACE-B is a little hotter, and so perhaps that's the reason why we saw a difference in a reversing of that urinary incontinence MCID. The other thing to understand is when you look at the PACE-B data, you can actually take a range of MCID from the original Skolarus QA paper. They say like, oh, an MCID is between four and six for this domain. We took the lower number and the PACE-B people took the higher number. And so that's perhaps one of the reasons why our incidence of these MCIDs was a little higher than PACE-B. And then at the end of our talk, we did want to acknowledge Felix, who is still near and dear to all of us, this study would not have been possible without his support and his advocacy and frankly his brilliance. So that's it.
Leslie Ballas: Thank you, Dr. Yu. Congratulations on completing this trial with 700 patients. I'm curious if you think that the differences that you found in patient reported quality of life between moderate hypofractionation versus SBRT are related to actual technique, or if you think that they're related to the difference in margin for each of those different techniques.
James Yu: So I think it's difficult to say. I would guess it's probably more margin than technique. That's based on examples like the MIRAGE study where even a millimeter made a difference in terms of that prostate rectum interface. Certainly the patients who underwent SBRT were required to have some sort of continuous tracking or motion management, whereas the IMRT, moderate hypofractionation arm was a little more lax. So it could have been technique as well, but I'm going to hedge on that and say both, but probably more margin than technique is my guess.
Leslie Ballas: Do you think that there's any difference in the fact that you use different domains to evaluate urinary and bowel toxicity?
James Yu: Yeah, so when we use slightly different metrics for that MCID, perhaps we were able to detect patients who had almost enough toxicity to make it to PACE-B but didn't, in terms of their counting of patients who hit that MCID. By the way, that was not in the primary manuscript that was in the supplement. If you look at Dr. Tree's original manuscript, you have to go into the supplement to find their analysis with MCIDs. There's multiple ways to evaluate a patient's quality of life. This was just the way that we decided to adjudicate as our primary endpoint.
Leslie Ballas: You guys used EPIC and did they also use EPIC?
James Yu: Yeah, they also used EPIC.
Leslie Ballas: Thank you. And so with the results of this study, both the primary results and the secondary results that you just presented, what are you going to do with your patients?
James Yu: So I've been doing SBRT for patients with localized favorable intermediate risk prostate cancer. And for patients who have kind of that moderate to almost severe IPSS score, I have been doing the NRG-GU005 cooler treatment plans. So I have been explicitly... Especially if patients have other indications that they definitely have localized disease, that they're going to respond well to treatment. Perhaps they have a lower volume of disease or a low decipher score, that sort of thing. I feel very comfortable delivering this kind of cooler SBRT plan. For my scan-
Leslie Ballas: Even with an 8% three year local failure rate? I think didn't GU005 have an 8% versus 4%?
James Yu: That was a biochemical, yeah.
Leslie Ballas: Yeah, sorry. Biochemical not local.
James Yu: Yeah. So yes, even with that, because one of the criticisms that we've had of ourselves for that biochemical failure is that potentially some of those could be PSA bounces, and there are folks who want to look into that already. So until we see that there's actually more proven local failures or more metastatic disease or more clinically relevant failures beyond that biochemical failure, yes, I do feel comfortable doing the NRG-GU005 dose. Again, for patients without big dominant lesions or other indications of more aggressive disease, these are the vanilla, favorable intermediate risks that are almost borderline. You could observe them. Some papers, I think suggest some Gleason three plus fours you can observe. So those are the ones that I do a cooler plan on. The majority of patients, though, we do do a hotter plan than GU005.
Leslie Ballas: Again, I just want to say thank you so much for spending time with us to discuss this. It's truly been a pleasure. I always love chatting with you, James, so thank you.
James Yu: Thank you, Leslie. It's always fun chatting with you as well.