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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center. We're here at the AUA 2024 Annual meeting in San Antonio, Texas. I'm pleased to be joined today by Dr. Todd Morgan, who's the chief of Urologic Oncology at the University of Michigan. Todd, thanks so much for joining us today.

Todd Morgan: Thanks a ton, Zach. This is great. Great chance.

Zach Klaassen: Always great chatting with you.

Todd Morgan: Thanks.

Zach Klaassen: We're going to talk about a really important guideline that you discussed at the meeting looking at the salvage therapy for prostate cancer. So just by way of background, what was the genesis of this guideline? I know there's an old guideline. Maybe highlight why we needed to update it.

Todd Morgan: Thanks. There was an old guideline. It was from 2013 and—

Zach Klaassen: Right. The dark ages of prostate cancer.

Todd Morgan: That was so long ago. It was a great guideline but tons changed. So that guideline focused really just on radiation for patients with a recurrence after prostatectomy. There were a lot of holes and not that they overlooked them, they just didn't have data for. For example, use of systemic therapy with salvage radiation. A few years ago, the AUA and the Guidelines Committee said, yeah, they knew there was a lot of data we could use to inform brand new guidelines. So it's not an update of the old guidelines.

Zach Klaassen: It's a brand new guideline. And I think you mentioned in your talk that, I mean, it's a huge lift. 2022 you guys started a major systematic review. Just tell us about some of the work that went into it.

Todd Morgan: It's really fun to be on these guidelines.

Zach Klaassen: A lot of smart people you're working with, right?

Todd Morgan: Yeah. I mean, we had a great, great group, multidisciplinary. Also, the AUA had support staff. Sennett Kim was our lead and was amazing. Roger Chou, who's a methodologist. So we've got this great team and that's where it starts: in the actual original literature and with a methodologist, which is different than a lot of other guidelines.

So this starts with key questions that the Guideline Panel puts together and then the lit search happens behind the scenes led by Roger Chou, and that really forms the evidence basis for the actual development of the guidelines. So it's not just a bunch of people sitting in a room saying, "here's what I think" and, "here's what I do," but here's the actual evidence and then ultimately, here's the level of evidence that we can attribute to any of the statements that we put together.

Zach Klaassen: Right. That's a great breakdown. So there are 30 new statements. We're not going to read them word for word for this interview.

Todd Morgan: Let's do it. We did that yesterday.

Zach Klaassen: Exactly. I think just highlighting. There's a big section of 12 statements on treatment decision-making. What are some of the things we should be pulling out of there?

Todd Morgan: One of the most important problems that we need to solve is the underuse of salvage radiation in general for recurrence after surgery, and in particular, the underutilization of early salvage therapy. So one of the guidelines that I really point to is for patients with a biochemical recurrence, these patients who need treatment should be before PSA reaches 0.5 or lower. So that's really important because we know that a huge percentage of patients don't get that opportunity to be cured of their cancer if they have later salvage or sometimes no salvage radiation. So that's a really big one.

Another big one, in that same section, is just a list of prognostic variables that we can rely on. There's a ton of data to support that. We spent a lot of time reviewing the literature to support what are the things that we think but actually aren't true versus the ones that we think and actually are supported by evidence. So there's a table that covers the things you'd expect, like grade, stage, PSA doubling time, but also time from surgery to recurrence. That's really important. And PSMA PET is going to be a big factor, but there's data to support genomic classifiers that are also prognostic. So those variables that we think about in this disease setting come up at any decision point. And that's really the whole point of this guideline: how do we help each of these decision points? When do we need to make a decision and what decisions should we make?

Zach Klaassen: Absolutely. There's a nice section and a couple of statements on recurrence after radiation. For the urologists, what are some good take-home points from that little section?

Todd Morgan: If I was going to pick one in that setting, it would be the need for a prostate biopsy. I think that's often overlooked. It's understandable that it's overlooked. A patient has a recurrence. Maybe they have an MRI or now a PSMA PET that really suggests that it's a local recurrence, but we still need to biopsy because we're thinking about recommending additional treatment. If we're not going to think about other treatment, okay, fine, then we can observe, but if we're at an inflection point where we're thinking about treatment, we're thinking about local therapy, or we're thinking about, you name it—radiation, surgery, cryo—we want to document that we are correct; that our intuition is that this is recurrence.

Zach Klaassen: Yeah, absolutely. You mentioned already the biomarkers in terms of genomics and there's going to be artificial intelligence biomarkers in this space as well. Let's talk about PSMA PET a little more because obviously, this has transformed everything we do with prostate cancer. Specific to this guideline, what were your statements on PSMA PET?

Todd Morgan: I think one of the most important ones that stands out for me, and it took a lot of work for us to get consensus on this and really look at the data, is a recommendation that for the patient, where we're thinking about recommending salvage therapy, salvage local therapy, we should perform molecular imaging is how it's phrased. The rationale being that at this point if we find somebody has distant disease, that should take us to a different treatment plan.

Zach Klaassen: It's going to dictate otherwise for sure.

Todd Morgan: Yeah. And again, there's really, really good data to support this. EMPIRE-I is an important trial, for example, where molecular imaging was performed in one arm and not performed in another and management in the molecular imaging arm was guided by imaging findings. And so that really lends strong data to performing molecular imaging in this disease setting.

Zach Klaassen: And that's with Axumin and not even PSMA PET too, right?

Todd Morgan: Bingo. Exactly. And that's exactly why we phrased it that way.

Zach Klaassen: Yep, absolutely. Across the spectrum, we're getting more multidisciplinary with prostate cancer specifically in this disease space as well. So just talk about the input of radiation oncology, pathology, genetics, all these people. I mean, this is really becoming prevalent, isn't it?

Todd Morgan: It is. It's really important to work together with a multidisciplinary team. As urologists, we're following the vast majority of these patients and we need to be the ones to recognize recurrence, of course. I think, in general, urologists do a great job of that. And then we need to be the ones to recognize, okay, now we've got to engage our multidisciplinary colleagues. We've got to engage medical oncology. We have to engage radiation oncology. We need help and we're not going at this alone.

Zach Klaassen: That's right.

Todd Morgan: So those partnerships are so beneficial to patients. Ultimately, I don't think we can know everything. The data's going to change regarding, for example, androgen signaling treatment intensification, right?

So we're going to see data evolve in that space that's going to speak to intensification and treatment. Ultimately, I suspect, even though at this point it's not recommended, in fact, there's a guideline statement that says that should only be used as part of a clinical trial, but we should be collaborating with our medical oncology and radiation oncology colleagues here.

Zach Klaassen: For sure. For sure. Anything we haven't hit on in the guideline you want to bring up? Maybe a couple of take-home points for our listeners.

Todd Morgan: Think about the biggest changes that have occurred in the past 10 years. Like you mentioned, it's molecular imaging more than anything else. Patients are getting molecular imaging and so how to interpret those findings. Patients with distant disease, for example, that probably don't need prostate bed radiation.

Patients with distant disease that would benefit from metastasis-directed therapy. So this like molecular metastatic disease setting, it's a really new setting. I think there's a lot of questions about should these patients who have molecular metastatic disease but disease that's not visible on conventional imaging, should they be recommended to undergo systemic therapy? The guideline says we should really discuss that there's not evidence to support that. But I think that's the most unique disease space. We know that this is a really unique disease space and the guideline really delves into that, and I'm proud of that.

Zach Klaassen: And I like the fact that you mentioned at the end that this is probably going to be updated. We're going to have phase three metastasis-directed therapy coming out soon. I mean, there's going to be more data in this disease space in the next couple of years, I'm sure.

Todd Morgan: Even more. Yeah. One of the things with this guideline is we only put recommendations and evidence around published literature. And so even abstracts don't go into form the evidence basis for the guideline. So as new data are published, and I'm sure we'll see some New England Journal of Medicine papers come in the next few years based on the trials that are enrolling, that'll inform future updates for sure.

Zach Klaassen: For sure. So get a little rest now and you'll be updating in a couple of years.

Todd Morgan: We'll be ready.

Zach Klaassen: Sounds good. Great discussion as always, Todd. Appreciate it.

Todd Morgan: Thanks. Thanks a ton, Zach.

Zach Klaassen: Thanks.