Navigating the Nuances: Exploring Imaging Options and Impact to Treatment Strategies in nmCRPC - Ryan Malone

January 30, 2024

Zach Klaassen and Ryan Malone discuss the management of Nonmetastatic castration-resistant prostate cancer (nmCRPC), focusing on the evolving role of PSMA PET imaging. They highlight the importance of defining PSA progression and the challenges posed by new imaging techniques in identifying low-volume disease. The discussion covers landmark trials and their implications for treatment options, emphasizing the need for thoughtful decision-making, especially when low-volume disease is identified by PSMA PET. They also discuss PSA doubling time, patient counseling, and practical aspects of managing nmCRPC in clinical practice, including patient follow-up and the integration of advanced practice providers. The conversation underscores the importance of staying updated with advancements in imaging and treatment strategies for nmCRPC.


Ryan Malone, MD, Urologist, First Urology, Louisville, KY

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

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Zach Klaassen: Hi, my name is Dr. Zach Klaassen, and I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm pleased to be joined today for a discussion about nonmetastatic CRPC with Dr. Ryan Malone, who is the director of advanced therapeutics and research at First Urology in Louisville, Kentucky. Thanks so much for doing this today, Ryan. Really appreciate your time.

Ryan Malone: Thanks for having me.

Zach Klaassen: This is an interesting disease space. As a urologist, it's a shrinking space with PSMA PET. How common are these patients in your clinic, and how frequently are you seeing and treating them?

Ryan Malone: Yeah, I think you hit the nail on the head when you said it's a shrinking space. A lot of the data that we quote to patients is based on previous trials and conventional imaging, but that's less and less common for how we're really evaluating patients for progression. They do still exist. Part of that depends on your definition of progression with the PSA, as we use ultra-low PSA. So I think you have to really pay attention to those numbers and be consistent with your definition.

Zach Klaassen: Yeah, absolutely. And we know that the three trials published in 2018 and 2019, the landmark trials, all showed MFS benefit, all eventually showed OS benefit for darolutamide, apalutamide, and enzalutamide. But these were all based on conventional imaging. I know, you know, PSMA PET is rampant, it's helped our clinic, and sometimes, and maybe in this situation, maybe it muddies the water a little bit. How do you sort of rationalize this with patients, often they show up with PSMA PETs? What's your go-to thing that you tell them based on what their PSMA PET shows, if it shows low volume disease in an otherwise setting of non-metastatic?

Ryan Malone: Again, I think your definition of PSA progression is really important with these ultra-low numbers. PSA doubling time comes into play, and I think I've seen different definitions, but anywhere above 12 months, I think, would be considered maybe not a fast doubling time.

Zach Klaassen: Right.

Ryan Malone: If we're seeing PSMA PETs that are positive in the pelvis, the N1 definition that was utilized in the trials that you're referring to, if they've got one lymph node that shows a little activity, the data doesn't really apply to that patient. Historically, and in the trials, they would not have been included. So they're technically indicated if you use that to define it, but other therapies come into play in that setting, such as SBRT. So if a patient shows up with a positive PSMA that's very low volume and in the pelvis, I try to explain those things, make an informed decision, and sometimes we encourage them to get conventional imaging so that we can compare apples to apples.

Zach Klaassen: Yeah, it's a great point. I think sometimes, too, I've had patients where you're trying to get them approved and conventional imaging is all they need. We expect it to be negative, and we know the drug works. But even in those patients that have low-volume PSMA-positive disease and maybe they have negative conventional imaging, we know the drug works in these patients. So I try to steer them away from PSMA PET if we can. Is that sort of similar in your practice?

Ryan Malone: I think it is. And there's also the PSMA studies, and if you've got a PSA that's too low, it doesn't really tell you anything more than you already know from the chart, really. So with those ultra-low numbers and knowing that their conventional imaging is negative, I don't always immediately go to PSMA PET.

Zach Klaassen: Yeah. You mentioned a little bit, and it is a nice jumping-off point into my next question about PSA doubling time. We know in the trials, typically it was less than 10 months. Do you have a cutoff in your practice? I know you mentioned 12 months. Are there patients that you would consider maybe even if it's 12 or 13, 14 months?

Ryan Malone: I've used 12, and part of the reason is, in the clinical trials, it was very controlled where those PSAs were performed, and they were consistent. And as we all know, you can have some lab variation, and I often have patients who have a PSA with their primary and then they have a PSA at LabCorp, they might have a PSA here, so I like to have a little bit wider net and not such a hard rigid 10-month cutoff because of that variation. So 12 has been the go-to for us.

Zach Klaassen: So anybody less than 6, you're pushing them towards treatment for sure, just based on fast doubling time.

Ryan Malone: Absolutely. Yeah, even 9, I would push them towards treatment.

Zach Klaassen: If we look at the Kaplan-Meier for MFS and OS for all three of these trials and all three of these agents, they're somewhat very comparable for these trials. So, are there aspects of the data or maybe quality of life or tolerability that may sort lean you towards favoring one versus the other two, perhaps?

Ryan Malone: It's splitting hairs. I agree with you. I think the data is very compelling for all of them, and one doesn't stand out from an efficacy perspective. But as you're well aware, some of them maybe had a higher incidence of rash. So patients with skin disease, I might lean away from apalutamide, for instance. With darolutamide, there's much less penetration of the blood-brain barrier. So in patients with concerns, fermentation changes, or prior TIA, certainly if they've had a cerebrovascular accident, that would be my preference. The discontinuation rate in that trial, for instance, was similar to placebo, so it's very well tolerated. But the take-home message to that being, they're all similar in efficacy, so you do have to look at those side effect profiles and choose the one that they're going to be most compliant with.

Zach Klaassen: Yeah, absolutely. And I think, too, these gentlemen are a little older, they're usually in their seventies, they've been on ADT for probably years already, and they're usually doing fine with that, so adding anything above and beyond what side effects they're used to can change the quality of life, correct?

Ryan Malone: Absolutely.

Zach Klaassen: In terms of the workflow in your clinic, how are these patients seen? You have a discussion with them, you discuss the options, they get on an agent, and then how frequently are you following them? Are the APPs eventually following them? How are you seeing them in the clinic, typically?

Ryan Malone: Yeah, it's a mix. I think it probably exists with you as well, but we have some patients that travel quite a way, and when I'm able, I try to set up a video visit with them and have a touch point and just say, "How are you doing?" Ask those specific questions about the different side effects. I do involve the APPs heavily. It is often not an efficacy follow-up, it's a tolerability follow-up, and our APPs do a fantastic job with that as well as also reminding them of their bone-targeted therapy and their calcium and vitamin D supplementation.

So I think we try to tailor it to the patient's need in terms of their travel, their access to, and willingness for telehealth, potentially. It's a wonderful visit for that, because we typically don't need them in person for a lab draw or something along those lines. And they have a direct line into the department. They don't go through a phone tree to get to us if they have a side effect. And I think that that's really helped with compliance, is to make sure that they have a comfort level that they can get ahold of us.

Zach Klaassen: Yeah, it's good points. I think to your point about the efficacy is not usually the issue because a lot of these patients, the PSA goes down, it stays down, and it can be a quick visit with them. And I think your point to telehealth is important because if they can get a lab draw close to home and just check on tolerability and making sure they've got refills and whatnot, it's a great opportunity to decrease travel, for sure.

Ryan Malone: Agreed. They appreciate it. They can have their family with them and sometimes the family can't take off to take a trip in if they're an hour away. So them knowing that you have some flexibility also helps them buy into the team approach.

Zach Klaassen: Well said. It's been a great discussion. I appreciate your time as always. What are anything we haven't hit on yet in your practice with nmCRPC? Any take-home messages for UroToday listeners out there?

Ryan Malone: A couple. I would say that stay tuned on the PSMA. I think that that is the future and we will figure out how to use it in this space. And remember that the trials' definition of nmCRPC still included the nodes less than 2 centimeters below the bifurcation. So these N1 patients are still eligible for these therapies and they did extremely well.

Zach Klaassen: Yeah, absolutely. That's great take-home points. We appreciate your time as always, Dr. Malone. Thank you so much.

Ryan Malone: Thank you.