Rodney Ellis: Oh, that is so much my pleasure, Leslie. Thank you so much for taking the time out to speak with me today and let me get the word out on the great results we've got for GU005.
Okay, thank you for coming today. My name is Dr. Rod E. Ellis. I'm presenting the co-primary results from RTOG NRG-GU005, an international phase three trial of SBRT versus hypofractionated IMRT for localized intermediate risk prostate cancer.
I have no disclosures. There's a list of my co-authors and their affiliations.
The NRG-GU005 study rationale is based on intermediate risk prostate cancer and has multiple accepted RT fractionation schedules for this group of patients. The SBRT is guideline endorsed and phase III comparative data has been emerging and we used RTOG 0415 and RTOG 0938 to inform the cohort selections. The hypothesis is that SBRT is superior to moderately hypofractionated IMRT. NRG-GU005 was designed with two co-primary endpoints. First to determine if SBRT is superior to hypofractionated IMRT, if SBRT is superior to hypofractionated IMRT in terms of patient-related GI and GU toxicity as measured by EPIC-26 bowel and urinary irritative obstruction domains respectively at 24 months post-completion of therapy by minimally important clinically differences on the EPIC-26 instrument. Secondly, to determine if SBRT is superior to hypofractionated IMRT for disease-free survival in terms of time to biochemical failure by Phoenix definition, local regional failure, distant metastasis, or death from any cause.
The study design is demonstrated here in the schema. Patients were stratified by risk group Gleason score seven, PSA above 10 or below 10, or Gleason score six with PSA between 10 and 20. We also stratified for rectal manipulation, which is mainly use of a spacer or a rectal balloon, and we used an IMRT standard arm, which is dealer's choice of either 70 gray and 28 fractions, which is more commonly used in the United States, but this was an international trial and it was modified to allow for 20 fractions of 60 gray total dose. We used 36.25 gray as the experimental arm at 7.25 gray per fraction, and that's important to look at as we discuss the results. It's also to talk about the margins. This was the first trial that we really tighten the margins. It was five millimeters superior, inferior, and lateral with three millimeter with anterior and posterior, and that becomes important.
Radiotherapy details. The target volume was generally just the prostate plus or minus the proximal centimeter of the seminal vesicles at the discretion of the treated physician. Again, if it was the standard arm, there was an eight millimeter uniform direction with five millimeters posterior allowed. Again, for the SBRT arm, a lower dose that is commonly used at some more common trials now 7.25 times five to 36.25 gray. It had a maximum dose that was limited at 39 gray. It did require fiducial markers and MRI fusion for planning as well as daily advanced guided IMRT, which was mandated.
The sample size was calculated to have an 80% and 83% power for the quality of life domains requiring 466 valuable patients. The disease-free survival was powered at 89% requiring at least 178 events from 560 valuable patients. Target accrual was 691 patients. The final accrual was 698 intermediate risk men with hormonal prostate cancer.
Patient characteristics for this study as demonstrated here were well-balanced across the arms on both sides. There were no significant differences in baseline health related quality of life.
For the health related quality of life about outcomes, we see it demonstrated in this figure where we see a statistically significant improvement at 24 months favoring SBRT at 35% over IMRT at 44%. Likewise, the longitudinal treatment effect showed a statistically significant difference favoring SBRT with a p value of 0.0016.
The primary urinary irritated obstructive outcomes unfortunately did not show a significant difference between the two cohorts measuring 35% for SBRT and 34% for IMRT. Secondary EPIC outcomes were presented earlier today by Dr. James Yu in a separate abstract however, and show that the sexual domain at one year as well as the urinary incontinence two year, both favored SBRT over IMRT. The longitudinal analysis also favored SBRT over moderately hypofractionated IMRT in terms of patient-reported urinary incontinence and related quality of life.
Disease-free survival. Futility bound was crossed for disease-free survival at 30% superiority with a hazard ratio of 1.38. P value was not clinically significant. The five-year disease-free survival was fairly equal at 89% for SBRT and 92% for IMRT.
Secondary endpoints included biochemical failure rate at three years for SBRT of 8% versus IMRT at 4% and this was statistically significant with a p value of 0.037. Overall survival, however, at five years was pretty well-balanced between both groups with SBRT at 91%, IMRT at 94% with a non-significant p value of 0.66.
Regarding the use of rectal manipulation, you can see that the patients were well-balanced with approximately 40% of patients having no use of a rectal manipulation and 55% of patients having a SpaceOAR. There was a small percentage of less than 1%, and approximately 3%, they either had a rectal balloon or both. The use of rectal spacer was associated with pure bowel, minimally clinically important differences when stratified for use for both IMRT and SBRT at a p value of 0.0011.
The summary of the key findings from NRG-GU005 are as follows. The bowel health-related quality of life was significantly better with stereotactic radio surgery. There is no difference between arms in primary urinary irritability and outcome health-related quality of life, but the secondary outcomes, again reported earlier this morning by Dr. Yu did favor SBRT at two years for urinary incontinence as well as one year for the sexual domain. There was no disease-free survival superiority of SBRT.
We would like to give our sincere thanks to the patients and their families that volunteered to enroll in the study as well as to all of the clinical research personnel that work to the complete accrual and collection of these data. I'd also like to give my personal thanks to Felix Feng. I owe a special thanks to him for his support and leadership throughout this study. He will truly be missed. Again, thank you very much for joining me today for the plenary session and review of NRG-GU005.
Leslie Ballas: Dr. Ellis, congratulations on NRG-GU005, quite an accomplishment. Really exciting to see this data presented. Can you please put this trial into context with PACE-B, another randomized control looking at SBRT compared to conventional and hypofractionated radiation?
Rodney Ellis: Thanks, Leslie. That's a great question. The PACE-B trial showed great outcomes for comparing SBRT to moderately hypofractionated IMRT or regular IMRT showing non-inferiority at five years with disease control rates at 96% and 95% respectively. There was a little bit more toxicity reported for SBRT on the GU front. What we were hoping to show on NRG-GU005 is that we could improve the toxicity both on genitourinary and rectal toxicity as co-primary endpoint. What we were able to confirm, however, is we decreased our rectal toxicity. We did not get an overall improvement in urinary quality of life, but we did get secondary analysis showing lower incontinence and better sexual function with SBRT over IMRT. We were very pleased with those results. We were also very surprised. This is the first phase III trial that reported outcomes of using a spacer with SBRT and again showed a significant benefit not only for the IMRT patients, which we expected from prior published studies, but this is the first phase III trial confirming that a rectal spacer further reduces rectal toxicity.
Leslie Ballas: Out of curiosity, did you collect any toxicity data on patients who had a rectal spacer before radiation? There have been certainly reports of toxicity from the implantation of rectal spacers and many would say that. Did you get any toxicity data on just that procedure or implantation?
Rodney Ellis: We did not have any that I was aware of specifically reported out on this, but again, that was not a primary endpoint of the study, so we've got the data that we've got. We could go back on secondary analysis and look for data, but fortunately it's fairly rare to have complications and the significant benefit was shown to be favorable. Now, when you really look at the devil of the details, there were very low toxicities either with or without a SpaceOAR, so really, it's a patient preference whether they would like to have that additional procedure done or not.
Leslie Ballas: The interesting thing to me is that you guys in NRG-GU005 used EPIC and reported patient-reported outcomes. The toxicity that was reported in PACE-B was based on RTOG definition and CTCAE, so provider reported outcomes. How do you think that changes the GU, GI toxicity that you're reporting compared to them?
Rodney Ellis: Well, I think that's a really critical point. When you look at intermediate risk prostate cancer and the high cure rates that are achieved and the long survival that patients have, patients are often looking at that data to make a decision between surgery standard radiation or SBRT. Having patient reported outcomes is very important for the patients' peace of mind to make a decision, and so I think it was really important that we put that in as a primary endpoint using patient reported outcomes.
Leslie Ballas: And do you have any data to present at this time, while it is not a co-primary endpoint, on the different fractionation schedules, the 70 gray versus 60 gray, was there any difference in terms of patient reported outcomes between the two?
Rodney Ellis: We've not yet done any other secondary analysis to look for it, so there was no obvious difference and the cohorts were pretty well-balanced.
Leslie Ballas: On the SBRT arm, how many institutions, or I guess really patients received MRI-based or an adaptive radiation treatment plan?
Rodney Ellis: Of course, all patients were mandated on this study to have an MRI to use that for fusion, for contouring. We did allow for the use of MR-Linac for this study, but I believe there were only one or two patients that actually were treated with an MR-Linac in completion of the trial.
Leslie Ballas: Right, because the trial started obviously quite a few years ago. Well, again, congratulations. Thank you for taking the time to talk with us today. This is an important study, and I look forward to reading the paper once it comes out.
Rodney Ellis: It's been completed and has been submitted, so hopefully we'll get feedback very shortly.