Edwin Posadas: Thank you, Dr. Ballas. It's great to be here.
Leslie Ballas: You are presenting the data from the RTOG STEEL trial. Can you tell me, what is the STEEL trial?
Edwin Posadas: So STEEL, or RTOG 3506, was a study of salvage radiotherapy in patients who were extremely high risk. The question being asked was whether we could augment the benefit of the androgen deprivation that's added to salvage radiation by adding a second agent, enzalutamide. So it's a drug you've heard a lot of in recent times with the presentation of EMBARK now in the biochemically recurrent space, but these are men that really need to be cured. These are men who have had PSA recurrence after surgery. Their risk of mortality is higher than your standard patient because of the high PSA, the pathologic factors that were involved, the kind of data that we gleaned from 9601 about who are the highest-risk patients. And I think in looking at STEEL, we ended up pulling a very high-risk population, as the control arm, the standard arm, had several recurrences within a two-year time span of being on the study.
Leslie Ballas: And what did you find in terms of your endpoints?
Edwin Posadas: So this was a study that was done intentionally through the RTOG Foundation to give us a quick answer, and the question was can we improve outcomes, so this was done as a Phase II trial with a bit of a broader endpoint in order to minimize the risk to the patients that were involved. We actually saw a substantial reduction in the rate of progression, following the addition of enzalutamide to the standard approach of giving salvage radiation with two years of androgen deprivation therapy. It was nice that we saw the improvement. It was several months of improvement that we saw, but the concern is also it increases toxicity to some degree. Nothing beyond what has been seen in the past with enzalutamide, but it does raise the question about whether you should be exposing patients to this. It needs to be further tested. I think the STEEL study, importantly, justifies moving forward with a larger study in this particular space.
Leslie Ballas: How did you guys define progression-free survival in an era before PSMA? Was it just biochemical progression-free survival?
Edwin Posadas: So this is a good question, and it's a really important one. We left the definition quite broad for a number of different possible events that could have occurred during the course of the trial. The bulk of events leading to progression for STEEL were biochemical events, and so we actually looked at several different endpoints. The clearest endpoint for us was using a PSA of 0.2, and this had mainly to do with variations across different sites. So at Cedars, for example, we use a PSA of 0.01 as undetectable, but there are many practices that will not use a PSA that is so low. So to be uniform across our groups, we used a biochemical progression of 0.2, but we allowed also for clinical radiographic progression and other events, including death, which fortunately did not occur on study.
Leslie Ballas: I noticed in the study that you did not include, as one of the very high-risk or high-risk features that could get you onto trial, PSA doubling time, which obviously is a very big component to the patients that were on EMBARK. How many EMBARK patients do you think are on this trial?
Edwin Posadas: Yeah, I think this is a really, really great and fun question, very, very thoughtful, and it's been one that really has become germane to the field of biochemical recurrence after prostatectomy. I think there probably were a good number of EMBARK-style patients on this particular study. They were very high-risk. Some of them had very high PSAs coming in, so their doubling times we would anticipate being very fast. We did not include that as part of the criteria, as this was a study that was built upon 9601, which did not include PSA doubling time. It's an interesting question to take back into the group to see if it makes a difference, but I will tell you, even without including doubling time in the list of high-risk factors that were essential to enrollment into 3506 or STEEL, we've already identified a very, very good number of factors, and PSA is certainly one of the strongest.
Leslie Ballas: At this meeting, we are also seeing the results of POSEIDON, which looked at individual patient-level data from six different randomized controlled trials of about the same era that this study was started, and found that there was really no overall survival benefit to ADT. How do you reconcile your results with those results?
Edwin Posadas: Yeah. It was a really nice presentation that Dr. Kishan gave this morning. It caused a lot of conversation at the meeting, as you may be aware, and I think it was a nice caution to think about this in broad, sweeping terms. I don't think we can blanket recommend hormonal therapy across groups. In fact, that's something that we at the NRG cooperative group, as you well know, has been looking at, trying to identify the right people for the use of adjunctive hormonal therapy. It comes at a cost to the patient. And Dr. Kishan very carefully, as did Dr. Koons in her discussion as well, emphasized the fact that in unselected population, that's not what you want to do, but there are clearly higher-risk patients within those subgroups. Identifying them either by genomic features, like we did for example in NRG-GU006, or by clinical factors, kind of stacks the deck a little bit.
There was even some debate during the discussion about certain patient types that one may wish to consider for this based on clinical biomarkers and/or genomic biomarker. So I think that means that you need to be more thoughtful about the patients that you're putting into or considering for androgen deprivation therapy as part of their disease entity. Things like doubling time may be a factor, though we didn't look at it, but certainly high PSAs would count for one. A luminal B phenotype would be another that one would strongly want to consider based on emerging data, and we'll see more as 006 gets reported out further. So I'd like to take that as a caution against broad general recommendations, and to really appreciate the fact that within the group of men who are biochemically recurrent following prostatectomy, there are variations in biology that need to be addressed.
Leslie Ballas: Thank you so much. It was such a pleasure to have you talk with us today.
Edwin Posadas: Thank you for your time.