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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm pleased to be joined today by Dr. Edwin Posadas, who is a medical oncologist at Cedars-Sinai Medical Center in Los Angeles, California. Thanks so much for joining us today, Dr. Posadas.

Edwin Posadas: Hi, I'm glad to be here. Thank you for the invitation.

Zach Klaassen: Absolutely. So we're going to talk about one of your published abstracts at ASCO GU 2024, talking about the STEEL RTOG 3506 trial. So, maybe just for a way of background for our listeners, how did this trial come to be? What was the genesis for this trial?

Edwin Posadas: Sure. So STEEL was a trial that we designed as a successor to RTOG 9601. Now, this was one of the first studies to show that for men with biochemical relapse undergoing salvage radiation therapy, the use of androgen ablation could improve outcomes. And in RTOG 9601, we actually saw that the men who benefited the most from the AR suppression, in that case, it was done with high-dose bicalutamide, the men who benefited the most from that seemed to be those with the highest risk features, including a high PSA, more aggressive Gleason scores, or pathology, or those that had PSA persistence following radical prostatectomy. And so the question that came forward from that trial was if the use of ADT, or the equivalent of ADT at that time, high-dose bicalutamide, improved outcomes for men, could we do even better with more intensive AR blockade that was now available in the 21st century compared to what we had back at that time? And so that was the original question put forward during the creation of 3506, or STEEL.

Zach Klaassen: That's great. So I think I liked the fact, like you mentioned, these were high-risk patients. These are truly the ones that had a potentially poor outcome, pN1, T3ab, Gleason 9, 10 disease patients. Tell us a little bit about the trial design, how many patients were randomized in STEEL?

Edwin Posadas: Sure. So the trial was designed as a randomized phase two study for men with biochemical relapse following prostatectomy with high-risk features. The randomization included standard LHRH analogs versus the LHRH analog plus enzalutamide, with both arms being treated for a period of 24 months. We stratified men on the study, and the analysis will stratify them by looking at the number of high-risk features that were present. As you know, it could be something like a high Gleason score, or it could be a combination of multiple factors which make men even higher risk, increasing their need. And for men that have had biochemical relapse following surgery, the salvage radiation attempt is really their last shot at getting to a cure, which is something, for all of us who take care of men with prostate cancer, when we see that opportunity, especially for these patients, we want to try to cross that line.

And so, if we could do that by increasing hormonal therapy, that would be great. The trial originally was designed to include over about 140 patients, and we actually got close to 160 by the time that the trial was done, which was great. We have some initial results that we had pre-planned, but during the course of the trial, because of terrible timing... So, this trial was conceived some time ago. Felix Feng and I were young investigators, young Prostate Cancer Foundation investigators when we put the trial together and proposed it to, at that time, innovation. By the time that we were getting the trial underway, after a number of different administrative hurdles, we hit the pandemic. And this was a real testament to what we can do even under the most adverse conditions. So, through the pandemic, we were able to complete a large multi-center randomized phase two trial through the RTOG foundation, which was a real triumph.

This is really the parallel structure of... Well, the old RTOG, which later became part of NRG, but the foundation still exists and is still active doing trials. To make the trial run and succeed, though, we had to make several pivots along the way, as did everything that happened during the pandemic, and one of those was actually we altered the endpoint from the original 9601 endpoint, which was a rise of two over your PSA nadir following the Phoenix definition. Now, we as a community came together and said, "Well, in the solid radiotherapy space, we really should not have any PSA signal at all. These men underwent prostatectomy. So if we were successful, it should remain suppressed." So, midway through the trial, quite midway, but before we got to the midway point, we looked at this and said, "We propose altering the trial."

And this was something with a nice investigative community and partners along the way we were able to complete. And so, we were able to make that pivot happen and we changed the endpoint to a detectable PSA, which in this case across the board would be a PSA of 0.1, just to be uniform across all sites. So, this makes the trial kind of interesting to look at and think about, because the readout came faster than previous salvage radiotherapy trials, but we did not meet a statistically significant difference at the first readout. And this was the planned readout that happened, but, again, because we moved it forward, we're anticipating that we may see separation at a time point that would be more commensurate with what was done with previous salvage radiotherapy trials. So, we're continuing to follow the patients, given the important contribution they made to science.

We certainly did see an important trend towards improved progression-free survival in the space with delayed PSA progression for men who received enzalutamide, but we didn't get significance yet. And Hiram Gay, who is the co-lead for this trial, he's the radiation lead, he and I have actually done a couple of things along the way that made this intellectually interesting, therapeutically interesting in addition to the enzalutamide alteration, because of new evidence that emerged in the field looking at the ability to boost regions of concern for men undergoing salvage radiotherapy. And this becomes particularly important, for example, in the era where we have PET scans available, we allowed the radiation oncologists to do what they thought was best. And for me and for Hiram, this made the greatest sense; you don't want to make a trial that doesn't apply to current practice.

And so the fields were adapted. They just needed to report where it was they boosted; all patients had boosted, the prostate had whole pelvis radiation, but they were allowed boosts to areas of suspicion in local regional lymph nodes, naturally, not distant, that would be a separate question altogether. So as we look at the trial, understanding this is a confounding factor, there may be several things that accounted for the difference in outcome in addition to the intensification of the AR blockade, but also the variation in the radiation field. And also, one important question that comes forward is compliance. And so we're still going through that data at this point, but, Zach, as you know, men that have to undergo the change in life that's induced by medical therapy, i.e., being hypogonadal, it's not the most fun thing. And so a lot of us in the field are really looking for ways to avoid extending that any more than we need to.

For those of us working in the salvage space for high-risk patients, we try to tell them, "Listen, we're going to do this for two years. Do your best to hang on." But with the intensified blockade, the stakes go up in terms of the inconvenience to men. Now, I want to be careful, and you and I were talking a little ahead of time before this, looking at the toxicity effects we saw in 3506, we did not see anything that was unexpected. So we all know that with intensified AR blockade, additional hot flashes, additional fatigue, all par for the course, they're tolerable. But the adverse event criteria that we use in cancer medicine were based on toxicity criteria that were designed for looking at cytotoxic agents and, even in some sense, later stages of disease where the risks and benefits, especially when options weren't so good, were certainly different.

And so while we don't see a substantial difference, we have to think about where men are at that point in their prostate cancer journey. And this is also an issue with a parallel trial that's certainly come to attention in our field at this time, which is the EMBARK studies. So the reason I'm going on this is because I think we're still trying to dig through the important data that the men who stepped up to help us with this trial put forward. When we see these promising signals, we really want to understand for the men we serve and for our community where those lines are between risk and benefit. And so I think this is still going to be a very fruitful trial for us to look at as a community.

Zach Klaassen: No, it's a great background of the trial and some of the challenges, and the pragmatic approaches to adapting it during the pandemic. And, also, as you said, some of these trials are ongoing, and they take years to accrue and they take years to reach endpoints; the field's moving, so that's a very important background on how STEEL shifted with the landscape as well as the global pandemic. So you mentioned a little bit about EMBARK, so I wanted to touch on that; it's not in exactly the same population, but how do these results from STEEL and EMBARK maybe complement each other, or how do we learn from both, and what are your thoughts on those two trials.

Edwin Posadas: That's a great question to bring up, and EMBARK has been a really important study that has come forward for our community in this space. So I happen to have the privilege of working side by side with Steve Freedland, and we all congratulated him and the EMBARK team for bringing that important trial to bear. So the similarity is that these are both trials that deal with men in a very important clinical space for men with prostate cancer, that of biochemical relapse. And I think it was tremendous that the EMBARK team was able to show, and the patients that stepped up to do this trial showed that the use of this intensified AR blockade could delay the onset of metastasis even with an intermittent approach to therapy, which was again another interesting maneuver. The EMBARK patients also included high-risk patients, high risk for distant metastasis, and are at high risk for biochemical failure.

Now, there's a lot of overlap between those groups. What we did not do, that was done in EMBARK, is that we did not re-initiate hormonal therapy at the time that the PSA was going up. And so, our primary endpoint for EMBARK, to be consistent with the salvage radiotherapy space in particular, which is a subset of the biochemical relapse patients, used progression-free survival after salvage radiation. EMBARK, being very bold in the BCR space, included a primary endpoint of metastasis-free survival, distant metastasis-free survival, which was tremendous. I think another parallel that we can see between the two is that in the space, there's no new toxicity signals for men. The EMBARK data looked quite similar in terms of adverse events that we saw in even the more advanced trials that Medivation put forward, including the other trials we looked at in the MCSPC space and the non-metastatic CRPC space.

So, it was good to see that we weren't seeing any new issues even with larger amounts of men being treated. But, again, this really becomes a question about how men earlier in the journey can tolerate these interventions, and then who's most appropriate for these. The EMBARK study really looked at men at risk for metastasis; while it provided a benefit for men, did all men need to go through that, using PSA doubling time, PSA kinetics in addition to clinical features? So, again, another parallel with STEEL. But, as a matter of personal perspective, as someone who's also actively engaged in biomarker work in this area, I'm really hoping that we see in the not too distant future—and I think the science is leading us in this direction—better markers for men based on the tremendous amount of biological work that's been done to unearth, to reveal the driving mechanisms of aggressive prostate cancer, because we really need to get tailored.

I tell all of my friends who are med-oncs, I step into a tumor board, and the lymphoma docs have all of their mutations and alterations on board. I tell the med-onc fellows, "You never present a breast cancer patient without speaking about the receptor status." And yet, in prostate cancer, we're still stuck with speaking about Gleason score, PSA, and clinical stage. They're important, and I don't want to disrespect any of the work that's been done in the field, but we've matured to a point where we know that there are certain alterations that are actionable and important. We know that HR deficiencies make room for PARP inhibitors, MSI-high prostate cancer responds to immunotherapy.

But we also know things about the loss of tumor suppressors, about SPOP mutations, and others. So, I'm hoping and praying that as this moves forward over the next few years, we're actually going to start with the molecular annotations of prostate cancer that say, "You know what? Based on your molecular features, your risk for metastasis is this. And while you'll have more hot flashes, your risk of osteoporosis, cardiac events may be a little higher, with aggressive medical therapy, we can balance all that to give you the benefits of this intensified form of therapy."

Or, on the flip side, to tell someone, "Okay, you have Gleason 9 prostate cancer that relapsed after surgery, but looking at your molecular profile, you don't need all this extra hormonal therapy. We can de-intensify your treatment because your biology speaks to that." The trials that we are doing now are paving the way for those answers. We certainly need to know the clinical outcomes. And with prostate cancer, we can't think six months in advance. We do trials that have ramifications for a decade or more beyond because men live a long time, and I tell that to all my patients. They walk into the room thinking, "I've got cancer, I'm going to be dead in six months." And this is prostate cancer; we're thinking about your duration and your quality of life, so we owe it to our patients and the field to lead that charge, and that's why we do what we do.

Zach Klaassen: That's fantastic. I appreciate that answer, and the similarities and the contrast with other fields are fantastic. We've got a lot of work to do in prostate cancer still. It's been a great discussion. Anything with regards to the STEEL trial we haven't hit on that you want to bring up, and any take-home messages for our listeners today?

Edwin Posadas: I think the big take-home message from STEEL was that I was really humbled to see how in this space the docs were creative to help patients and the patients still stood up. We have a lot of important questions to ask in prostate cancer. I want to make sure that the doctors who listen to this understand these trials are really pivotal when we bring them forward. They're vetted hard, they're thought about very carefully, and we try to answer the most important questions. So please support them by opening them up at your sites and or sending patients into sites that are participating in them. And for the patients that may be listening to all this, we have a lot of great ideas as physicians and scientists, but it's all great coffee room talk until the rubber hits the road, and that's in the clinic.

And so when the patients step forward and participate in these things, especially those with patient-reported outcomes, we unmask new issues, new ideas, we bring forward new goals. And these ideas about really pushing on quality of life earlier that several in the field, like Alicia Morgans, are working on are the result of our patient interaction, our patients stepping up and saying, "Hey, you guys need to address this." And so this bidirectional interaction between physicians and patients really makes a difference. And so it's really the partnership that makes those things happen, and so I want to make sure that if you give me a last word, it's that we got to keep going and we need to work as a team with our prostate cancer scientific community, the clinical community, and, most importantly, the patients and their families who are affected by this disease.

Zach Klaassen: That's a perfect way to summarize it. Really appreciate your time today, Dr. Posadas, sharing about the STEEL trial with UroToday. Thank you again.

Edwin Posadas: Sure thing. Thank you.