Zachary Klaassen: Hi, my name is Zach Klaassen are in Cartagena, Colombia for the SCU 2025 annual meeting. Delighted to have on UroToday Dr. Ricardo Rendon, who is a Urological Oncologist at Dalhousie University in Halifax, Nova Scotia, Canada. Ricardo, thanks for joining us on UroToday.

Ricardo Rendon: Thank you, Zach, for the invitation. A pleasure to be here.

Zachary Klaassen: So we're going to talk about management of biochemical recurrence, and certainly we've seen a lot of movement both in imaging and treatment over the last couple years in this disease space. Maybe just define what high-risk biochemical recurrence is for our listeners.

Ricardo Rendon: I would like to start with biochemical recurrence, like we do a lot of medicine, we're putting a cluster of patients with a lot of variables into one group. So these are patients who could have had radiation, surgery, or hormone treatments, or treatments, a combination of them. They also have different longevity, comorbidities, and they also have different Gleason scores. So we're lumping a bunch of patients with many different problems.

Fortunately, the AUA has helped us define risk groups. It has been very clear for many years, even going back to the Pound data that patients with a rapid PSA doubling time develop metastasis faster and have a much greater prostate cancer specific mortality. So it's basically patients who have a PSA doubling time of less than one year and a Gleason four, five, those are the patients who are high-risk. One of the things that is important to remember is that Pound data from JAMA in 1999, they look at patients who were not treated for prostatectomy and they were followed prospectively, so they followed longitudinally.

And so they have a time to presentation of metastasis of eight years after the recurrence and five years from metastasis to death. And this is before we start to treat our patients now with ARPIs and other novel treatments. So we always have to remember about the characteristics of the patient, not the cancer as well.

Zachary Klaassen: Yeah. Great background. I think, too, for our listeners, there's going to be a lot of patients where PSA doubling times 20 months, 26 months, these are patients that maybe it's okay to watch, but really that high risk, less than one year, less than 10 months, PSA doubling time are really the ones we have to be concerned about, correct?

Ricardo Rendon: Yeah. And when we were looking at the, because we had an EMBARK open at our center, and the screening fails were incredibly large, it was only about 30% of the patients because most of them didn't have the right PSA doubling time.

Zachary Klaassen: That's right. Great segue. Tell us a little bit, at a high level, the EMBARK trial. We've heard a lot about it over the last couple of years. What were some of the high level results from that trial?

Ricardo Rendon: Okay, so just as a reminder, EMBARK trial is patients with high risk biochemical recurrence. They had to have a high PSA and a higher Gleason score. The patients were randomized into three groups. It was the standard of care, which was a [Inaudible] or Bicalutamide with LHRH agonist, or enzalutamide alone, or a combination of ENZA and the standard of care. And the patients were followed, and the primary endpoint was metastasis free survival. The primary endpoint was met with a significant reduction at a follow-up of about six years. And so that's when it was released and it was approved in the States and in Canada for treatment of patients with a high risk biochemical recurrence.

We just saw a release, a press release from Pfizer in mid-July stating that they have met a secondary endpoint of overall survival. So we haven't seen that data fully yet, but they have met. Because when we're treating these patients, as I said before about the Pound data, we do worry about what's going to happen with this patient in the long term. Because I do have a lot of patients from the EMBARK trial days that are still alive and living in treatment for many years. So I think we still need to learn a little more about the characteristics of the patients and their disease to decide who's going to be going in these kind of long-term treatments.

Zachary Klaassen: Yeah. Great summary, and I think hopefully we'll see maybe the OS data at ESMO, maybe GUASCO, but I think hopefully-

Ricardo Rendon: Yeah, it should be available soon.

Zachary Klaassen: I think one of the things we talk about a lot on UroToday and just in general is obviously EMBARK started accrual a long time ago, conventional imaging, and now when we fast-forward to 2025, almost all these patients either come to us with a PSMA PET or we order a PSMA PET. How do you interpret conventional imaging trial data with the contemporary use of PSMA PET these days?

Ricardo Rendon: So we're all struggling with that.

Zachary Klaassen: Yes.

Ricardo Rendon: Technology is hitting us hard on the face, and we're trying to adjust to it. We all have different access to PSMA.

Zachary Klaassen: Sure.

Ricardo Rendon: Better in the States. In Canada, it's getting better. In many other countries, is very little availability of PSMA PET. So we're all adjusting to this.

Zachary Klaassen: Yes.

Ricardo Rendon: I would like to go back to the APCCC meeting, the last one, when they asked the panelists that, if PSMA PET access was not a problem, would you request a PSMA PET CT for this patient's biochemical recurrence? And everyone said yes. And would you treat them according to this new staging based on PSMA PET? And the vast majority of people, over 85%, said that they would adjust the stage according to PSMA for someone.

Zachary Klaassen: Right.

Ricardo Rendon: But as you said, this doesn't reflect the patient population at the time.

Zachary Klaassen: Right.

Ricardo Rendon: So I think we have to combine a bunch of different things. First of all, PSMA PET is recommended in most of these patients. As you said, even if they haven't had it before, you can do it later. We don't do it in every single patient, we tend to do it when the PSA is over 0.3 because the sensitivity starts to increase to over 30-35%. But also when they are high risk, it has been shown when they're high risk, the sensitivity again goes up even higher. So we tend to use it more carefully for patients with a high risk and a PSA of about 0.3.

So we are using this PSMA for those patients, and we are adjusting a treatment based on PSMA findings. Whether it is data-driven or not, that's what we're tending to adjust. And that is where we have most of the clinical trials underway right now for BCR patients, we're doing trials for both diagnostic purposes and for treatment purposes with a lot of inclusion criteria of these trials is negative, regular conventional imaging and positive or negative PSMA PET imaging. And so we're waiting for that data to come out. For now, we just have to adjust, do what we have, and most of us have chosen to go the PSMA PET finding route.

Zachary Klaassen: It's a great answer to a difficult question. You just alluded to clinical trials. This is such a hot space right now. Maybe just tell us a little bit of some of the exciting trials or the trials that you're excited about that are in the works right now.

Ricardo Rendon: So, as I said, there are different trials that are very relevant. So the first one is to do PET imaging in patients who have biochemical recurrence post surgery, and to try to determine as to whether the patient should have radiation to the pelvis, to the recurrent area, or just have systemic therapy. And we will have more and more data coming up. There is an EMPIRE-2 data trial that is going to help us with that. Saying that, PSMA PET CT is still not very good to identify disease in the pelvis with a sensitivity of above 40 to 48%. So right now, with such a good access to PSMA PET in many centers, we should not be using PSMA PET findings to determine what we're going to do to lymph node surgery or radiation.

The other trials that are very important is different diagnostic methods to detect disease. When I'm requesting a PSMA PET CT in patients with biochemical recurrence, basically what I want to do is making sure that they don't have disease outside of the pelvis. I'm not looking inside of the pelvis because the sensitivity is so low. I just don't want to radiate someone who is not going to benefit from that because the disease is elsewhere. And the other set of trials, we have different trials with different ARPIs and with PSMA, the positive patients, we're starting to do trials with theranostics. So we're starting to use lutetium and actinium, and a bunch of other targets to treat these patients.

Zachary Klaassen: Yeah, there's such a huge wealth of data that's coming down the road that'll hopefully help, but we have even copper data coming out with really good sensitivity, the oligometastatic setting, SBRT-ing these lesions. So I think everybody gets excited about all these RLT trials coming out in advance, but this oligometastatic high-risk, biochemical recurrent setting is really going to be interesting as well.

Ricardo Rendon: It is dramatically changing. We still don't know what to do with it nowadays, but it's very exciting keeping us on our toes.

Zachary Klaassen: Absolutely. Ricardo, great conversation. Thanks for joining us in UroToday down here at SCU.

Ricardo Rendon: Thank you, Zach, for the invitation. My pleasure.