Prospective Monitoring of Biochemical Recurrence with PSMA PET - Ravi Madan

July 10, 2023

Alicia Morgans converses with Ravi Madan about an ongoing trial involving patients with biochemical recurrence of prostate cancer. The unique trial utilizes Prostate-Specific Membrane Antigen (PSMA) PET imaging to routinely monitor patients and to develop an understanding of the natural history of the disease in the context of recurrent prostate cancer. The goal is to prospectively monitor these patients over five years, with regular scans and PSA tests. Dr. Madan emphasizes that the trial does not exclude intervention, allowing patients and their doctors to make informed decisions based on the scan results. Dr. Madan ends the conversation by urging the medical community to be judicious in interpreting PSMA results and invites interested patients and clinicians to join the trial.


Ravi A. Madan, MD, Medical Oncologist, Head of Prostate Cancer Clinical Research, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Ravi Madan, who is a GU medical oncologist at the National Cancer Institute. Thank you so much for being here with me today. 

Ravi Madan: Thank you, Dr. Morgans.

Alicia Morgans: Wonderful. Dr. Madan, you have, certainly, a wealth of trials open at the NCI for our patients with prostate cancer, but I wanted to talk to you about one trial that's currently in progress, really exciting for patients with biochemical recurrence, and you use PSMA PET to examine these patients on a routine basis and think through managing and monitoring those patients. So, can you tell me a little bit about this?

Ravi Madan: Yeah, it's kind of a new frontier in prostate cancer in the last couple of years since the approvals of PSMA PET imaging. I think it has clear roles and well-defined in earlier stage disease and newly diagnosed patients, but I think we're all kind of struggling with what it means in patients who have biochemically recurrent prostate cancer, because 10 years ago, they had a PSA 5, we couldn't see anything, we didn't do anything. Now we get a PSMA scan, and it shows things, and it really creates a compulsion to do something.

But we have a wealth of data, actually, from Johns Hopkins that tells us that based on PSA kinetics and other parameters, patients could go 5 to 10 years without clinically relevant disease. In those trials, they looked at time to progression on CT and bone scan, but that's really going to be clinically relevant at that point, they may need hormones. But if we're talking about things that are quartiles of decades away, do we really need to move the goalpost, as they say, and escalate therapy and start it now because we can see it? And somehow that meets a definition of what we could call metastatic disease. So I think part of this is probably coming up with a new term of biochemical recurrence. Maybe it's like PSMA-positive recurrence or something.

But I think what's missing, and there are several trials going on looking at radiation, different forms of hormones, earlier treatments, but what's really missing in this equation is an understanding of the natural history of this disease in patients with with PSMA PET in the context of recurrent prostate cancer. To kind of fill the void on this data, I partnered with my friend and collaborator at the National Cancer Institute, Peter Choyke, he's in molecular imaging, and we are conducting a large trial which is going to prospectively monitor these patients.

So these patients are patients who have a PSA more than 0.5, it doesn't even have to be rising at a particular rate, they have to be more than a year removed from their definitive intervention, surgery or radiation, they can have had previous hormones or not, just as long as their testosterone's over 100, and it doesn't matter if they've had previous PET scans. As long as they have a CT scan that's negative and a bone scan that's negative, and CT scans negative for soft tissue disease, and a technetium scan that's negative for bone disease, they can enroll on the trial.

The trial consists very simply of PSA is every 3 months and PSMA PET scans at baseline. If it's negative, we repeat it in a year. If it's positive, we repeat it again every 6 months. We can technically follow patients for up to 5 years. We just started, so I don't know how far we'll get with the 5-year follow. But, logistically for patients, the PSAs can be done at home, the PSMA PETs have to be done at the NCI campus in Bethesda, but because it's an NCI trial, we're able to pay for travel for patients from around the United States. So we have people coming in from all over for this trial that just started recently. We'll also get some blood and do some biobanking and hopefully ask some questions about what the patterns of changes we see. I think we can't use the word progression because we don't really know what that looks like, and that might be something else we can learn and how these changes over time may impact what I think is really important in this, which is clinically relevant disease.

The other thing I'll say is the trial, the way it's written, actually allows for intervention. So our goal would be to get the scans, share it with the referring physicians, and they can choose to do with the patients whatever they want. And we'll talk to them too. But if they want to get SBRT at their home institution, we'll give them the scans to help them do that. But it doesn't take them off the trial. The only thing that would take them off the trial is more than six months of systemic therapy. So, also, it'll give us a way to understand, even if we do intervene, what the natural history is. And so I'm really excited because I think that, in some ways, this is the control arm for a lot of trials that's ongoing that we just don't have.

Alicia Morgans: It's really fascinating because it's almost a surveillance for biochemical recurrence, but it also allows for some small interventions along the way, which is really interesting. Now, I think you told me a story, and you perhaps you've written this up too, but you talked about a patient who had a lesion on PSMA PET, and I think as you were continuing to follow, to your point, it didn't progress, it actually resolved. Can you tell me a little bit about that?

Ravi Madan: Well, yeah, actually, one case study that's really interesting, we published the JCO as part of a commentary on this last year, and it was a patient from 2019. He was in his sixties at the time, he had definitive radiation in 2011, biochemical recurrence in 2016. And at that point in 2019, his PSA was, like, 29, but his doubling time was long, which is very good in terms of when clinically relevant prostate cancer would develop in him.

So he did a PSMA PET scan, which, at the time, was still research, and he had some spots on his liver, spots on his spleen, really more than five or six in other areas as well. Now, I work with excellent imaging doctors, and they told me that they're not really in the liver parenchyma. They're actually on the serosal surface, which I think is an important distinction to some degree. But regardless, maybe I was being a little dogmatic at the time, but I said, "All right, well your doubling time is long and this is still experimental."

We followed him for a couple of years. His PSA actually hit 50 2 years later. It's actually still a slow doubling time. It actually slowed down. He was on another trial with us. But when we repeated his imaging on his PSMA, things were a little bit brighter. There were a couple more areas, but nothing dramatic. His conventional imaging was still negative. So, at some point in 2023, that patient may wind up, if you over interpret what existing data we have with ADT and antiandrogen and chemotherapy because there's things in the liver and that's metastatic, but that's where you have to take a step back and say and realize that that data doesn't apply to these patients. Those patients were never eligible for those mCSPC trials. And if we would've done that 5 or 6 years ago, the patient would be as he is now, and I probably would've looked like I did the right thing, but I wouldn't have done them any favors because of the toxicities that would've resulted from 5 years of androgen suppression.

Alicia Morgans: That is so interesting. Now, we've saved this patient, you, not me, but you have saved this patient all that time on treatment and those really toxic treatments. It's really fascinating that conventional imaging remains negative and also really fascinating the location on the serosal surface of the liver.

Ravi Madan: Yeah, that was interesting.

Alicia Morgans: That is interesting. So at some point I hope we figure out what exactly it is, because it doesn't necessarily sound like it's prostate cancer. And that's part of the point. That sometimes what's glittering is not prostate cancer, it's just glowing.

Ravi Madan: That's part of this too. I actually do think it's prostate cancer. He had other places that were biopsied. I just think that it's interesting when we do these PSMA pets and they light up in all these soft tissue areas, especially lymph node disease. But unfortunately, you and I both know that when we get to late-stage prostate cancer, that's not where the morbidity or mortality comes from. So what's the disconnect there?

Some people will tell you it's three options. One is it's not clinically relevant and we're just kind of capturing it, other people will tell you it is very important because it's a staging ground for where it gets to the mets, or is it just PSMA is not great at detecting what's in the bones, which ultimately is the driver for morbidity and mortality. I think, from my perspective, this probably has been going on since prostate cancer existed, we didn't have this scans. And then when we give it ADT, these areas respond better than the bones do.

Alicia Morgans: Wow.

Ravi Madan: And so, we're just hoping to get more information and I think that you hear a lot at these meetings and people are like, "We should do it with bone scans and everything." But from my perspective, if I have a patient with a 4 millimeter lymph node, I'm not inclined to castrate them for life. And if they have a bone lesion on PSMA but it's not seen on technetium, we have to realize that there's no data that actually says we should treat them. We're existing data and applying it to this situation.

Alicia Morgans: Well, you are definitely keeping us honest with this study. I wonder, can you tell us if patients are interested, how they would connect? How would they get involved?

Ravi Madan: Yeah. They can actually contact, it's a website, so I'm sure we can get them a link and they can contact us directly if there are providers out there. Patients can also email me. If you Google my last name at NCI, you get a scary picture of me, but it's got my email on there, just send me an email. Providers can do the same thing and we'll get you in our system and get the ball rolling and make sure it's something that's right for you and your doctor.

Alicia Morgans: Wonderful. And of course there are many other trials available at the National Cancer Institute. As you said, one of the fantastic things is that the NCI will cover costs of travel and support patients from around the country to get care with you and your team. So, I think just as a general resource, you guys are an amazing, amazing group to help our field. We will make sure we have the information and any contact information needed available for patients and for their clinicians. If you had a closing thought, what would that message be to those viewers?

Ravi Madan: Yeah, I would just say that sometimes new technology gives us new perspectives, but without the answers, we might not know what to do with it correctly. And we really need to be judicious in how we interpret what we see on PSMA.

Alicia Morgans: Wonderful. I could not agree more. I thank you so much for your time and good luck on your trial.

Ravi Madan: Thank you.