Tyler Seibert: Thank you. My pleasure.
Leslie Ballas: So good to see you.
Tyler Seibert: You too.
Leslie Ballas: Thank you. Tell me... Set the stage for us. What is a high level summary of the data for radiation to the primary?
Tyler Seibert: Great, sure. So I mean, this isn't so new anymore and people are aware, I think, but most of us remember very well a time where we wouldn't have considered doing radiation to the primary when there was metastatic disease. So it still feels somewhat new and there've been a lot of nice publications around this. So summarizing the data, there have been three randomized trials looking at the question of radiation to the primary in metastatic prostate cancer. The results are nuanced between the three and there's some room for different varied interpretation, but the summary is that there's a clear benefit for progression-free survival and delaying progression across the trials, that seems to be fairly consistent, though it's not 100% in every subgroup or every study.
It also seems consistently true that the group that's most likely to benefit is that that has a low burden of metastatic disease. The definition of that is controversial. There's the CHAARTED definition that was used in a lot of these analyses. There've been secondary analyses looking at number of metastasis. Some advocate for volume of metastases, but the big picture is small volume, low volume of metastatic disease probably benefits from radiation to the primary. There might even be a survival benefit to that.
Leslie Ballas: Great. Thank you. And a question that I come across in my clinic, and for the radiation oncologists watching this, I mean, the data would say radiation to the primary, maybe plus/minus MDT, depending on the exact scenario. When are you also including elective radiation to the lymph nodes in these patients, if at all?
Tyler Seibert: It's a great question. So that's tough. I mean, the MDT, I think you start with radiation at the primary. Answer is yes, for me. We treat the primary, especially if there's a low burden of disease. Even if there's a high burden of disease, I would favor doing it for most patients. Not if they have a poor performance status, not if they have really severe urinary symptoms that we're going to acutely make much worse, but for your typical patient today that I'm seeing with newly diagnosed metastatic disease, I treat the primary.
Now, once we've decided that we're treating the primary, it becomes very interesting. What do you do with the other visible disease? So let's start with they have metastatic bone disease, for example, three metastases. If it's only on PSMA PET, then from my perspective, those patients would've been on the M0 trials. So absolutely we should treat their primary. There's no question about that. But what to do about those visible lesions is an open question. So my position on this is we don't know. We don't know which patients benefit. I think some probably do. I'm sure some probably don't, and so we need to figure that out. And the best way to do that is a randomized trial.
So there are several that are ongoing, the TERPS trial, METANOVA, TRITON here at UCSD. We also have TERPS open and that's my position. With these patients, I tell them we have better medications than we used to have. We are treating the primary now. We don't know whether it's worth treating the few metastases we can see. We assume there's more that we can't see, and so we put them on a trial to randomly assign them to either treating that or not.
Now, I dodged the lymph nodes question, come back to it. So my view on the lymph nodes is if we're treating every visible disease, then, if they have positive lymph nodes and I'm treating the bone metastases on trial, then I will also electively treat the rest of the lymph nodes because I'm treating the positive lymph nodes anyway. If I don't have any positive lymph nodes, then I don't treat the lymph nodes on the trial. And if they're on the trial and they're randomized as standard of care, I just treat the prostate because that's the only thing that's supported by randomized data to date.
Leslie Ballas: That's a very similar practice to mine, but-
Tyler Seibert: Oh, good.
Leslie Ballas: ... sometimes feel very tempted to treat those lymph nodes.
Tyler Seibert: Yeah.
Leslie Ballas: Yeah. You also mentioned, which I think is an important component to thinking about this is there's newer drugs since these trials have been published. And so how are you integrating ARPI versus just ADT in these patients?
Tyler Seibert: Good question. So I mean, if they have very high risk based on STAMPEDE, then they're eligible for a ARPI, and particularly abiraterone, that's one that was tested, so that's our standard practice. I think that's pretty standard everywhere. It's in NCCN guidelines. And between the three trials we talked about, PEACE-1, HORRAD, and STAMPEDE, if you look across all of them, it does seem like adding abiraterone doesn't obviate the benefit of radiation to the prostate in the metastatic setting. Even docetaxel in the meta-analysis, STOPCAP, it doesn't look like addition of docetaxel was obviating that benefit.
So I don't think that adding another medication means you don't do it. It changes the timing. If we're doing docetaxel, then we delay. I'm not doing radiation at the same time. I will let them get through the docetaxel first. But adding abiraterone, I think doesn't change much from my perspective. We just do both. And remembering that none of these medications for systemic disease have proven curative, whereas radiation does clearly eliminate disease and in the localized setting. So it makes sense to me that they would be synergistic.
Leslie Ballas: Yeah.
Tyler Seibert: And we can't expect to do a new RT to the primary trial every time a new drug comes out.
Leslie Ballas: Of course. Another scenario that comes up, which is not as well-supported by the data, but I think we'd love to hear your perspective on, is what happens when a patient has oligometastatic disease immediately following a radical prostatectomy. Are you giving radiation to the prostate bed and the oligomets?
Tyler Seibert: I'm not. I think it's a good question. And the INDICATE trial is an example of where we can do that. Of course, the standard of care on that one is treating the prostate bed. It's hard for me to justify going after hypothetical microscopic disease when there's macroscopic metastatic disease. And that's been my position for years. I know other people see it differently. They think that patients are potentially cured, but I think that's a trial question. We don't know that. You already know it's gone. There's metastatic disease that's visible that we haven't even proven that you need to treat unless it's to delay hormone therapy. STOMP and ORIOLE, and they're phase-two and they're small, but they were very nice trials that showed a benefit for delaying ADT in the biochemical-recurrent setting. So that's very reasonable as a quality of life balance. We don't know what the overall survival impact of that is, and I always tell patients that, so that's fine, but going after elective microscopic disease in that setting is tough for me.
Unless what you're doing is... Again, now if you talk about PEACE V-STORM, where the question was treating the lymph nodes in oligometastatic lymph node-positive disease post-definitive treatment, then adding the elective nodes did delay distant metastasis. So that's again, reasonable in the setting where you're not giving hormone therapy. If you're giving hormone therapy in an ARPI, maybe it helps, maybe it doesn't. We don't really know. I tend to be on the first do no harm, don't over-treat side of things. That's my personal bias.
Leslie Ballas: Yeah, I actually have used that exact sentence, "I don't understand treating potential microscopic disease when there's macroscopic disease", many times. And while salvage radiotherapy is extraordinarily well tolerated, the toxicity of that treatment comes from radiating the bed more than probably the MDT. And so I agree. I think without the trial, that's a very hard sell for me.
Tyler Seibert: Yeah. I mean, and how many patients... It's a good question. If everybody treats like us, how many times do we see recurrence specifically in the prostate bed later? I mean, I haven't seen it yet in any of my patients that I can remember where we treated the mets and then they only recurred in the bed and they didn't have any additional metastasis. I've never seen it. So maybe it's a thing and maybe it's something we need to worry about, but it must be a small fraction of patients. So we'd be treating a lot of patients to prevent a small number having a local recurrence in the bed. And as you said, all of them are having adverse effects from the radiation of the prostate bed. So it doesn't sound like a good deal to me.
Leslie Ballas: Yeah. Thank you so much for joining me today to discuss this. This was really fun for me. I love getting to talk to radiation oncologists about these questions. So thank you, Dr. Seibert, and we really enjoyed your talk at APCCC. Congratulations.
Tyler Seibert: Thank you so much. My pleasure, truly. We can talk more anytime. It was great. Great conversation.