Tian Zhang: Hi and welcome to this segment of UroToday. I'm Tian Zhang. I'm a GU medical oncologist and associate director of clinical research at UT Southwestern Medical Center in Dallas, Texas. I'm joined today by my long-term friend and colleague, Doctor Ravi Madan, who is a senior clinician at the NCI and directs prostate cancer clinical research. Thank you for coming in today, Ravi.

Ravi Madan: Thanks for the invitation, the opportunity to talk about our research.

Tian Zhang: Wonderful. So we're going to talk about your trial and prospective monitoring of prostate-specific membrane antigen positive, biochemically recurrent prostate cancer, preliminary data from your six-month PSMA follow-up. So tell us a little bit about this. PSMA PET is so hot right now in our clinics. What got you started, and why are you doing this?

Ravi Madan: Yeah, so years ago, it was clear PSMA was going to be a big deal in prostate cancer. It's probably bigger than anyone imagined. And so it's in every clinic. It's being used in every patient. And there's actually very little data telling us how to use it. And it's impacting newly diagnosed patients and late-stage patients.

But it's also probably dramatically impacting what we used to call biochemically recurrent prostate cancer. And in those patients, they had microscopic disease that couldn't be seen on CAT scan or bone scan. And so patients were monitored for years. But with PSMA imaging, it was clear that we were going to find that microscopic disease, whether it was a 3 millimeter lymph node or a 7 millimeter lymph node. And unfortunately, it was clear that people were going to want to treat that.

But having treated those patients for a while back, way back before 2020, when there was a PSMA PET, it was clear that those patients didn't necessarily require therapy. And of course, we know from all the BCR trials that were done previously that treating those patients didn't improve survival. There have been trials with ADT, chemotherapy. EMBARK shows a PFS benefit, but survival is immature at this point.

So we realized that we probably needed to get some data. And so my colleague, Doctor Pete Choyke and I-- Pete Choyke is head of the imaging program-- sat down and said that we could do something like this. And he's like, "What do you want to do?" And I said, "Well, let's just get scans on people." So we have a trial where basically we enroll patients who have a PSA over 0.5, negative CAT scan, negative bone scan. They've had their definitive therapy.

This is also in the post-salvage setting. So most of these patients have had salvage if that was appropriate. And then they enroll. And we basically at PSMA every six months. Now, therapies are allowed. Patients can get SBRT or less than six months of systemic therapy. Actually, about 85% of the patients don't get therapy even if they're positive. And what we present at ASCO this year is the six month follow-up from what's happening in those patients.

Tian Zhang: Yeah, and it's an early disease setting of prostate cancer to your point but so much a little bit more advanced. I mean, I'm seeing some PSMA PETs even being done when people are around 0.08, 0.1. So what does that continuum look like? And can you speak a little bit about what you're seeing in those patient populations?

Ravi Madan: Yeah, so our minimum's 0.5. And there's some data showing that that's where you're more likely to see it than not. However, at our enrollment at 0.5 of the-- so we've enrolled about 140 patients. And we present the first 86 where at least six months out. And of those 86, 76 all have findings that are on the PSMA. So 10 are still negative. So once you get into that range, it's more likely to be positive.

But what we're realizing also though is that and the reason why we're presenting this initial data set is that not much is happening in those patients. Now we have patients with average PSA is about 3. Doubling time is 11 months, which is a little longer but high risk by European criteria if you believe the way they label it. But there's also a third of patients with doubling times under six months. And doubling time is an important predictor of outcomes in biochemically recurrent prostate cancer going back to the Hopkins database.

So what we're seeing is that these patients have findings. And of the patients enrolled, about 10 of them don't have mets, 17 have localized disease, 59 have mets beyond the prostate. Of that, over 20, 23, I think so far, have more than four findings. So it's what people would consider beyond oligometastatic.

And what we're seeing at six months is very little changes. Thus far, only one patient has had progression in that time period of these 86 patients. And that patient had a very fast doubling time, had a lot of disease, also had some bone findings. About seven of our patients so far have bone findings. It's a minority.

But it highlights the fact that this is an indolent disease state. And just because we can image them and find things on PSMA, we shouldn't be compelled to treat it. And even if these patients do have changes over a period of time, they're not going to be symptomatic. And perhaps most importantly, there's no data saying we're improving survival.

Tian Zhang: That's really interesting. So tell us again, in that patient population, you're not starting hormone deprivation. You're mostly following them.

Ravi Madan: Correct. So we have a discussion. We have a discussion with the patients about what the data tells us. And the data does say that it doesn't improve survival. And that's part of the discussion.

They also have a primary oncologist who they've either already spoken with or speak with afterwards. Radiation is an option. A handful of patients have had radiation with very mixed responses. Basically, our best patient with the best response probably didn't need treatment because he had one lymph node and a doubling time of 40 months, but his PSA went down. Our faster moving patients didn't have an impact.

But that's not the point of this study. But the point is that while treatment is allowed, patients actually, once they understand the situation a little better, are willing to monitor it for another six months. I do think a big part of it is that they're like, well, I only have to believe you for six months and then we can look again. But I think that the therapies that are being used often involve some form of hormone blockade or hormone suppression, and that brings a lot of side effects and long-term consequences for chronic issues.

Tian Zhang: And this issue of timing of starting hormone deprivation, when and how much do we intensify or not, all of that comes into play when we can see a lesion. And to your point, the people who have PSA over 0.5 tend to have something on their PSMA PETs. So Declan Murphy a couple of years ago at GU ASCO said this is more precise imaging. What do you think about that? And how does more precise imaging guide us or not in how we treat our patients?

Ravi Madan: So I'm not sure it's to the benefit of the patients because I'm not sure adding on these therapies is changing anything but the short-term readouts. I have no doubts it's more precise, but does knowing specifically where one finding is tell us that we can intervene and have a meaningful outcome? When we do see changes on the PETs, it's often in a whole different region. So you can radiate a whole region of lymph nodes. But if you get the next PSMA scan has a supraclav node, what did you really do?

And then a lot of people pile on hormones. And that really raises the question of why are we targeting radiation if we're giving systemic therapy anyway? But I think that one of the reasons why I wanted to do this study was because we already knew these patients did well for a long period of time. The imaging changed the feel in the clinic. It changed the anxiety for the patient and the provider.

And it caused questions. Can you follow a patient with 10 PSMA positive lymph nodes? And the answer from our study thus far is yes, you can. And I think that the vision of PSMA positive findings is that the dam's about to break and we must intervene, or we're going to miss a therapeutic window. I don't think our data at this point is really saying that that's anything like the case.

Tian Zhang: Yeah, in my practice, a lot of times these lymph nodes are pretty small. They're not measurable per our standard criteria, but they light up. And so, people say well, we can see it. And so therefore, we must do something about it. So that causes to your point a lot of anxiety for our patients.

Ravi Madan: But I would say that hopefully with data from our group and others, we can maybe inform the patients that we don't have to do anything about it, and that it's not going to be a symptomatic progression over time. And it's not going to impact their longevity, either treating it or not. And again, when we have a conversation with the patients, they're more inclined to wait.

Now it's not a now or never thing. Some of our patients later on will go on therapy. We have no doubt of that. And then we also have studies looking at different ways to intervene without hormone suppression at the NCI for such patients. But I think that as a field, we need to step back and realize part of our job is to educate the patients about what's really going on and what these findings really mean.

I think one of the biggest issues we have is that the radiology report comes back with the word metastatic on it. And then like I said, it raises the anxiety in the visit. The patient's already googled what that means. They think they're going to live three years. Maybe they think they're going to live five years if they understand metastatic castration-sensitive prostate cancer.

But that's a false equivalency. PSMA positive BCR is not equivalent to metastatic castration-sensitive prostate cancer. We all know as you said, those trials required CT and bone scan findings. These patients don't have that at all. And I mean in our trial they're CT and bone scan negative.

Some of those trials like LATITUDE and PEACE-1 didn't even enroll recurrent patients because the people who ran those trials knew that those patients did too well and would mess up their statistics. So I don't know that getting these scans is always helpful for the patients not because I'm opposed to getting the scans, but it's the conversation and education that has to follow. And granted, there's not data yet, but this and hopefully other studies will help provide it.

Tian Zhang: Sure. And to that point then, do you always get your CT and bone scan to correlate whether the PSMA PETs are showing disease that's on conventional imaging?

Ravi Madan: Yeah, so that's a great point. So everybody has a negative CAT scan and bone scan at enrollment. Now, the CAT scan does allow threshold up to 1.5 centimeters. Most patients thus far are not even that close. And the bone scan is for bone findings.

I think one of the things that you see with PSMA PET reads is you'll see something on the PET scan, and then they'll see something on the CT window. And if you look hard enough, you'll see something. But 2018, we weren't just calling things on CT bone windows. Apparently now, we are because we have the PET. But I would say that practice should be to find therapies that are appropriate for patients. If you have a PSMA finding in a bone, you should get a bone scan.

There's data from the Hopkins group that highlights that the findings on conventional imaging are genomically more aggressive than PSMA only findings. And so again, there's genomics underlying some of this. There's our data. I think we're a little too gung ho to treat these findings. And on some level, our study is the control arm for a lot of studies that are being done without a true control arm.

Tian Zhang: Sure. No, it makes a lot of sense. And so if we try to put that into our practices, are there good risk factors, for example, of patients who are coming into our clinics and they are still anxious, but are there patients who you think, hey, maybe it's fine to wait six months, 12 months, and especially if they're worried about side effects of hormone suppression?

Ravi Madan: So right now, we're having trouble finding high risk features that would require therapy. We only have one progression in the first six months at the first 60 patients with disease beyond the prostate. So it's a very small minority of the patients. Historical data tells us doubling time is important. We know from the Hopkins database, if your doubling time is three months or less, your likelihood for metastatic disease at five years is about 65%. If it's six months or less, it's about 50%.

And interestingly, even though EMBARK enrolled up to nine months, if it's between-- I'm sorry, it was three to six months, it's 50%. If it's six to nine months, it's only 25%. So I think you can really look at doubling time and stratify your patients. Unfortunately, what I see in the world, in patients who come to us is people take a patient with a long doubling time, assuming they even calculated it, get a PET scan, and they throw away the doubling time and say, we have something to treat. We're going to treat it.

I actually think we can do better than that, much better than that. I think what we can do is take patients with faster doubling times less than three months, which is truly high risk if you look at the data and say, "Well, we did a PET scan. You got a 4 millimeter lymph node. We could probably check that again in six months. You're not going to have significant changes or clinical symptoms."

Tian Zhang: That's really great insight of how we can pair PSA doubling time with our PSMA PETs, which often we're already getting right in our practices there. These patients are coming in with multiple PSA reads. And their prior PSMA PETs were not actually in medical oncology. We're perhaps not the ones ordering them, at least initially.

But what you're describing is really how we also think about sometimes intermittent hormone therapy for patients who have biochemical recurrence and how we decide on the higher risk features. So I think still a lot more that we're learning about this patient population. So super important work that you're helping us add in and fill in the data. And so congratulations--

Ravi Madan: Thank you.

Tian Zhang: --for all your work.

Ravi Madan: I do just want to say one thing. We're still enrolling. We can enroll probably up to somewhere between 250 and 300 patients or 350. So if patients are interested in being a part of this study, once they make their first trip to the NIH in Bethesda, Maryland, we actually pay for their travel afterwards. And of course, it's federally funded. So there's no cost for the PET scans that are being done.

We've had a great referral base from colleagues across the country, Edwin Posadas, Doctor Paczynski in St. Louis. We have lots of Hopkins folks that are sending us patients, Jeanny Aragon-Ching, Laura Sena at Hopkins. So we have a nice consortium of people sending us patients, but we get a lot of patients who just find us on their own, too. And again, I think we have to step back and really realize that when we find something on PSMA, we shouldn't be looking for a reason to not treat. We should actually be looking for a reason to treat because right now the data is telling us that the vast, overwhelming majority of these patients do not need urgent therapy.

Tian Zhang: I think that's really important to fill in those data pieces where we have them and help us understand who we can leave alone and who we really need to start treatment on. So thank you again. Anything else you want to add?

Ravi Madan: No, I just want to say that I'm very appreciative of my team at the NCI who's really done a lot of hard work on this study. Megan Hauser has been the lead researcher and has done a great job. Amy, Hank and Nicky Williams have done a great job. Melissa Abel, Fatima Karzai are our team, and they've all just done great. And the patients are remarkable, and we couldn't do it without them.

Tian Zhang: Yeah, well, these trials could not be done without a whole team behind them. So absolutely, thank you so much. Thanks for coming in.

Ravi Madan: Thanks for the invitation.

Tian Zhang: All right.