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Alicia Morgans: Hi, I'm so excited to be here today with Professor Sandy Srinivas, who is joining me from Stanford and also joining me from APCCC 2024, where she gave a wonderful talk about whether we should treat the primary tumor in the setting of synchronous high-volume metastatic hormone-sensitive disease. Thank you so much for being here with me today, Sandy.

Sandy Srinivas: It's a pleasure, Alicia, always a pleasure to talk to you.

Alicia Morgans: Wonderful. Well, let's hear your talk and then we'll ask some questions.

Sandy Srinivas: Okay. So this was my talk. I was asked to address the role of radiation to the primary in patients with metastatic hormone-sensitive disease and specifically the role of high-volume patients. So I went over the trials that really led us to where we are today. Specifically, I started off with the HORRAD studies. So this was, again, a trial with 432 patients who had metastatic disease. But interestingly, they only included patients with bone-only disease. They looked at two different fractions of radiation. And you can see up here that the survival curve really showed no difference in overall survival. But when they dug deep into the number of bone metastases, you can see that patients who had less than five bone mets appeared to have a hint of improvement in overall survival with a hazard ratio of 0.68, which didn't have statistical significance. But this was the first hint that maybe patients with lower volume disease may benefit from having the prostate radiated.

The next trial that really gave us some insight was the STAMPEDE trial here, looking at ARM H, which specifically looked at radiation to the primary versus standard of care. The standard of care here was ADT alone, and a very small percentage of patients actually got docetaxel. Again, two different schedules of radiation. And here again, like the HORRAD, there was no improvement in overall survival for all patients, but if you looked at the low-volume patients, there was an improvement in OS, improvement in failure-free survival (PFS), and even prostate cancer-specific survival. Interestingly, the hazard ratio was identical to HORRAD and was 0.68. So this quickly led to the incorporation of radiating the primary in low-volume patients in many of our guidelines and kind of got incorporated into our clinical practice as well. The next thing that came along was PEACE-1, which had a little complicated design.

This was a two-by-two factorial design, had four arms, and was essentially asking two questions: What's the value add of abiraterone over ADT and docetaxel? And there was a clear improvement. The second question was, what's the role of radiating the primary in patients with metastatic disease? There were some surprising findings compared to what we had known in the past that there was no overall survival even in low-volume patients with this intensified systemic therapy. There was an improvement in rPFS in low-volume patients, but only in the intensified arm with standard of care, ADT and ABI. But one thing that PEACE-1 taught us was that there was an improvement in what they defined as serious GU events, and that was defined as patients having bleeding, obstruction, catheterization, or need for TURP. And that benefit was seen not just in low volume but also in high volume patients.

So overall, my summary was that HORRAD and STAMPEDE had suggested improvement in OS in low-volume disease. PEACE-1 suggested no improvement in OS in patients even with low-volume disease when the primary is radiated. We did see an improvement in rPFS in low volume, but only in the intensified arm and not in the standard of care, unlike STAMPEDE. However, there was improvement in GU-related events seen both in low volume as well as in high volume. So here is my take-home message. It's true that there was no survival advantage in radiating the primary in high-volume disease as well as low-volume disease, but there was significant improvement in local control seen in both low volume and high volume.

And I would say that there are other instances in oncology, such as using bone-modifying drugs, for instance, in patients with CRPC where we don't see a survival advantage. But clearly, controlling skeletal-related events is an important quality of life aspect as well. So the current standard of care is not just ADT. So I think we don't even know whether there's a benefit of RT in patients, whether it is ADT intensification. So I suggested that maybe we should look at Arm G in STAMPEDE versus Arm H to really understand the role of radiation in hormone-sensitive disease.

Alicia Morgans: Well, thank you, Sandy. That was really phenomenal. And what I think is so interesting is that this particular thing, which seems like it might be a small aspect of care, has really just evolved, flipping and flopping with each year that goes on as data comes out. And I don't know if you were surprised, but I was surprised when the low-volume patients in PEACE-1 didn't seem to have a clear benefit. But when it comes to rPFS, at least those patients who had that intensified hormonal therapy seemed to benefit, at least in that outcome. So I guess at the end of the day, you're seeing a new patient, metastatic hormone-sensitive disease de novo, and say low volume because high volume I think you spoke to very clearly. Do you radiate the prostate or not? Do you have a shared decision discussion? Do you think about a TURP if they're having urinary symptoms instead of radiating the prostate? What do you think about?

Sandy Srinivas: I mean, I think in the clinic we see patients coming back who have not had their prostate radiated. Many years later, they come back with severe bleeding, needing bilateral nephrostomy tubes. So I think this is a real problem. Radiating the primary, even if there isn't an overall survival benefit, I think if there is benefit in delaying radiographic progression or even in these local GU symptoms, I think it's worth it. Radiation certainly to that area has not that much toxicity, and they're not doing the same dose as they would do with an intent to cure, so I certainly bring up radiation. There's a lot for patients with newly diagnosed metastatic disease. I do find that the conversation is so heavy; you have to talk about the side effects, you have to talk about genetic testing, you have to talk about... So I kind of divide it a little bit. I start with systemic therapy, but I do introduce this idea of radiation and what that would do for their symptoms. And I think most patients accept that radiation would be a good option for them.

Alicia Morgans: I have to say I do the same thing. And I love your comment about using a stepwise approach because exactly as you said, in hormone-sensitive disease, there are all kinds of things that we're talking about, even sort of helping people understand that they may be able to live for years, which is something that they may not understand at the initial part of the visit, plus the genetic testing, plus the potentially complex systemic therapy that they're taking, and bone health, and cardiovascular health. I mean, it all becomes a lot and then also includes radiation to the prostate. So I do talk about it as well, but love that you have that stepwise approach. I also really think it's interesting to consider assessing Arm G and STAMPEDE. Can you talk the listeners through that just a little bit, sort of setting up what those different arms are and exactly what your comparison would be? What would you be looking for in terms of your primary endpoint there?

Sandy Srinivas: Yeah, I think our standard of care has evolved with time. It was ADT alone back in the day when STAMPEDE was evaluated, comparing Arm H, which was just radiation to the primary. And when they did that analysis, the standard of care was ADT alone. And I think that's not where we are today. ADT doublet has become a standard of care, and clearly, there are some patients for whom we are doing triplet as well. So what is the role of radiation in that setting? STAMPEDE has done an interesting analysis many years ago where we had this question about should we be doing ABI or should we be doing docetaxel? While it wasn't a true randomization, they were able to compare the arm that got docetaxel versus ABI, giving us some sense that we could be doing either ADT plus DOCE or ADT plus abiraterone.

I think an analysis similar to that, so Arm H is radiation alone and Arm G is the one where they intensified with ABI. I'm hoping we'll be able to get some sense that with that comparison, would we still see a survival benefit for patients with low-volume disease when you do intensification?

Alicia Morgans: Really, really interesting. And I'm hopeful that they can do some more of those analyses, like you said, with the contemporaneous randomization, allowing some of these things that we might not otherwise have anticipated. So very, very interesting. So what would your advice be to people who are going to the clinic tomorrow? And is that advice based on consensus? Was there consensus at the APCCC?

Sandy Srinivas: For low volume, I think there is consensus that patients will get their prostate radiated. For high volume... I mean, there were 187 questions, so we didn't get to see what the consensus was. They only presented a few questions. So I'm curious to see whether there was consensus or not. My sense would be that there isn't for high volume patients, given what we have seen with the PEACE-1 data. I would imagine that most providers are not going to jump into radiating the prostate. But I do think that maybe in the future there may be some patients who would be appropriate. So my sense to our listeners and viewers would be start with systemic therapy. That's what patients with high volume really need.

And then maybe six months down the road, we can reassess this question. Especially those patients who have high volume disease in the prostate, maybe a very high Gleason score. People who you think are likely to get into obstructive symptoms in the future, especially if they've had a great PSA response, you know what their longevity is going to be. I think addressing local therapy in that group would not be a bad idea, but I think we need more data to guide us.

Alicia Morgans: Well, that is always the answer we seem to come to at the end of these. When we have a gray data area, we will always need those clinical trials, but I so appreciate you walking us through your thought process here. Giving us some thoughts even about future clinical trials that might help us understand the best way to move forward and certainly for helping us as we go to clinic tomorrow and try to get the best outcomes for our patients. Thank you so much for your time.

Sandy Srinivas: Pleasure. Thank you for having me here, Alicia.