Alan Bryce: Hello, I'm Alan Bryce, medical oncologist from City of Hope in Arizona. I'm here today with my colleague and boss, Dr. Tanya Dorff from City of Hope in Duarte. And we're going to speak to you about some of the recommendations from the 2024 for US Prostate Cancer Consensus Conference. This conference was an expert consensus conference of key opinion leaders from around the United States, where we debated areas of gray-- the shades of gray in daily clinical practice that prostate cancer physicians struggle with. Tanya, nice to be with you today.

Tanya Dorff: Yeah, thanks for the invitation.

Alan Bryce: I'm going to ask you about some of these consensus recommendations. If you could provide the listeners with why we reached these recommendations, what's the point-- I guess-- we're trying to highlight and why you think it's really important to incorporate these approaches into practice.

So the first recommendation from the committee was that in patients with mCRPC-- so metastatic-castration sensitive disease-- that PSMA PET scanning at a minimum should be used when deciding on the appropriateness of metastasis-directed therapy, and can be considered for staging of all patients in addition to conventional imaging. So it's this question of should we be getting PSMA PET scans in mCRPC, and how do you apply that?

Tanya Dorff: Well, I think so many patients these days come to us with a PSMA PET scan, and we are constantly grappling with how to make use of the information. But this particular recommendation, I think, centers around the idea of incorporating metastasis-directed therapy, because from studies like ORIOLE, we learned that if you apply metastasis-directed therapy on the basis of conventional imaging and you miss areas that you would have seen on the PET, that you haven't done a good job.

And so it makes sense to confirm, I guess, an oligometastatic patient before applying metastasis-directed therapy. Aside from that, we really try to stay away from using the PSMA PET to assign volume of disease and treatment decision making. By and large, although hopefully that is evolving.

Alan Bryce: Yeah. And actually that segues perfectly into the second recommendation from the Committee of in defining high-volume disease, the committee felt that conventional imaging, rather than PSMA PET, should define what constitutes high-volume disease. So could you speak to, I guess, the difficulty there and why the committee felt as strongly as it did, that conventional imaging should be used?

Tanya Dorff: Yeah. I think this was one that some of us struggle with more, because we know PET scans show us so much more disease, and it's actually real disease. It's just a smaller amount. But the studies that we base our treatment paradigms on did not stage-shift or volume-shift patients based on PET. And so we just try to stay true to the data. But it can be challenging.

And I think, again, the one place where I would make an exception is for metastasis-directed therapy. At this point, I wouldn't necessarily use the information for chemo, although that's a tough sell-- if you actually see something visceral on the PET that you didn't see on conventional.

Alan Bryce: Fair enough, fair enough. I mean, this question of high volume, we define it as a number. I guess the question comes down to if a patient has four bone metastases on conventional imaging, and they have six on PSMA PET, do the additional two change how you think about the biology of the disease?

Tanya Dorff: I mean, I think in that case, no. So where do you draw the line? It's actually surprising how well the CHAARTED definition of high volume does risk stratify. There is something about one of the bone mets being outside of the axial skeleton, and we all know visceral mets are different, although probably, we need to refine that when considering lung versus other sites. So it's imperfect and yet it's quite prognostic. And so I definitely don't think about six bone Mets versus four when you add in the two on the PSMA PET as making that patient different. But again, I think the visceral would be a little more challenging for me.

Alan Bryce: Well, fair enough, since you said it, let me just follow up with the question of-- can you elaborate on the point about why lung metastases, you don't clump them in the same way as other visceral metastases? Maybe the listeners don't at this point.

Tanya Dorff: Well, that's one way to say it. We do think that patients with lung metastases do better. It's not as poor prognosis as other visceral sites. The other way to look at it is that liver mets are really associated with the poorest prognosis. And I think there are other sites that maybe we're not sure-- like peritoneal spread or adrenal. Maybe we still have to learn a bit more about where those fall in the spectrum. But yeah, visceral mets are not created equal, I would say.

Alan Bryce: Absolutely. All right. Wonderful. How about this question of-- in patients with low volume mCSPC, the role of radiation therapy to the prostate-- the committee felt very strongly as a consensus that radiation of the prostate should be offered in the low-volume patients. So what do the listeners need to understand about that?

Tanya Dorff: Well, the data sets are actually limited. There's been widespread adoption, and I think it's important to remind folks that there are boundaries to this recommendation. So the original STAMPEDE arm that did radiation to prostate primary and showed the benefit in low-volume was in the absence of intensified systemic therapy. And that's where PEACE-1 was designed to fill in that gap by having patients with abiraterone, and also the possibility of the radiation to the prostate primary.

That being said, I think the preponderance of evidence, even if there's not as much evidence as we would like, does suggest that there is a benefit.

Alan Bryce: Now, the question of-- and we've touched on a little-- metastasis-directed therapy, you see wide variations in practice. But nevertheless, the committee felt that for patients with oligometastatic mCRPC, MDT should at least be offered. I guess, where is our thought process on that? And we recognize that we don't have level 1 evidence here. But how do you think through that discussion with your patients?

Tanya Dorff: So we're talking in a de-novo situation versus metachronous. I mean, most of the data have been in metachronous. And yet, we have moved it into the de-novo setting. I think for one reason, it just makes biologic sense. We know we don't get to zero cancer with even intensified ADT. We're not curing patients with ADT doublet. And so when we have active areas of disease, it's appealing to try to deepen the remission by applying a therapy that should kill more of the cancer where we know it is.

But there's also that rationale from the all-comer solid tumor study that did standard therapy alone, or standard therapy with metastasis-directed radiation, and found a survival benefit. Granted, it wasn't prostate, but I think that lends some data support to this hypothesis that I elucidated, that we want to try to kill more.

And there's more studies like the RADIOSA and EXTEND that I think are filling in some of our knowledge gaps, although not so much still in the mHSPC. And I'll just put in a plug for SWOG S1802, which will help us learn about this because metastasis-directed therapy is allowed but not mandated. So we'll be able to look at metastatic hormone-sensitive prostate cancer patients in the real world-- how they're being treated-- doublet, triplet metastasis radiation or not. And then also get the answer of whether treating the prostate primary is helpful.

Alan Bryce: Absolutely. All right. And then one last recommendation from the committee to ask you about. The committee said-- for patients who develop oligo-recurrence after significant disease-free interval after previous MDT alone for low-volume mCSPC repeat MDT may be offered. So where does this fit into the paradigm-- repeat MDT? When do you feel like you got enough out of MDT that you would do it again?

Tanya Dorff: I think it makes sense to think of it in a time frame sense and also, I think, pace. So for me, it matters not only that from the last MDT, it's been a good amount of time, but also there are not five new. I think the shorter time in the multiple just tells you that probably it wasn't as oligometastatic as it might have appeared.

Alan Bryce: Wonderful. All right. And then I want to ask you about areas where there wasn't consensus, because there are certainly areas where I think the questions remain open. And the committee really had a diversity of opinion. I think a major one is what about radiation to the primary and high-volume mCSPC? So the de-novo patient high-volume disease, should we be radiating the prostate? We've answered this in low-volume, but what about the high?

Tanya Dorff: Well, I think we actually haven't fully answered it in the volume, but I think that it's pretty clear there was not a benefit in the available data sets for high volume. Doesn't mean there can't be a benefit, but we would need to see a positive trial in that context. I think certainly, the approach in SWOG S1802 makes sense that you would at least want to make sure your patient is achieving a good remission before you would consider it.

So in that trial, you wait six months and make sure that the cancer is responding and under control before you would consider it. And to me, that makes a lot of sense, because these high-volume patients sometimes have really aggressive disease. They might have early resistance. And in that context, when the whole systemic burden is advancing, it really doesn't make sense.

Alan Bryce: All right. One last question. When triplet therapy-- there really was no consensus amongst all the faculty about where are we reaching for upfront triplet therapy in mCSPC? What is your approach?

Tanya Dorff: So I certainly discuss it with patients with very aggressive symptomatic presentation. I think some of us also look at the genomics when they're available to say, OK, this is a really aggressive-looking tumor based on the molecular profile. Hopefully, we'll have more tools to predict a little bit better-- not only risk but also responsiveness, because who's to say docetaxel is the right tool in the patients with the most aggressive disease? It's just the tool we have. And it makes some sense, for rapid proliferation. But I will definitely talk about it with patients. But I also feel very comfortable putting them on a clinical trial with a novel triplet.

Alan Bryce: Fair. Wonderful. Well, thank you very much, Tanya. It's always a pleasure to speak with you and learn from you. And thank you for your time.