Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday. A real pleasure for me to be able to welcome Fred Saad, everybody knows Fred, Professor of Urology. Although many people think he's a medical oncologist at University of Montreal, Fred has contributed immensely to our knowledge of prostate cancer over the years. Welcome, Fred.

Fred Saad: Thanks, Oliver. It's a pleasure to be here.

Oliver Sartor: Today we're going to be talking about a trial in progress, one called PSMACare, and you're helping to lead that. I wonder if you could explain a little bit about the background of the trial, inclusion-exclusion, and then I'll kind of pop in with questions if I feel like questions are warranted. But go ahead, let's start covering the PSMACare study.

Fred Saad: A lot of the background behind this is I have to hand it to you for all of your work in radioligand therapy over the years, and really it's going one step further than where we've been, right? We know clearly that lutetium-based RLT is clearly advantageous post-ARPI and post-taxane. Now we have really exciting data in the taxane-naive population, post-ARPI. And so this study is exploring, it's more exploratory where it's not going to answer the question of a randomized phase three, but this is a randomized phase two where we're exploring in non-metastatic CRPC, so these are non-metastatic based on conventional imaging, but have to have PSMA-positive disease on new generation imaging. And we know that these high-risk, non-metastatic CRPC have over 95% chance of having something on PSMA. That is the inclusion criteria. You have to have non-metastatic CRPC, rapid doubling time and positive PSMA, and then we're giving lutetium-based RLT to both arms, and one arm is going to have added to that, the standard of care, which would be an ARPI, the choice of the investigator.

So it's really to look at what kind of PSA responses we can get. And this is not a comparative study, but really what percentage of patients reach undetectable PSA below 0.2 with or without an ARPI? So really trying to push the field forward in the utility of an RLT in these micrometastatic patients, because that's what I would prefer calling them than non-metastatic, because we know they've got disease. And so this is really allowing patients with PSAs above one. We just lowered that, it used to be two and we lowered it to one. And now we're allowing patients with PSA doubling times of greater than 10 months, as long as they've got PSMA-positive disease, to try to address this issue where they don't necessarily have an access to an ARPI. So really exploratory with a primary endpoint of PSA, but obviously secondary endpoints of time to metastasis, RPFS, overall survival. So really, it's about a five-year study exploring the utility of introducing PSMA-based RLT in an earlier setting than what we are conventionally doing now.

Oliver Sartor: Thank you, Fred, for laying that out. Let me ask a couple of questions. Question number one would be regarding the amount of PSMA PET uptake relative to liver, is this sort of a standard VISION criteria in order to get in the study? Are there alternative definitions of PSMA PET positivity?

Fred Saad: No, it's really very, it has to be above liver. Very minute PSMA avidity wouldn't allow, so these are patients who have to have PSMA-avid disease, very similar to what was seen in VISION.

Oliver Sartor: Fred, another study that you were involved in, and by the way, you've been involved in so many, but this one was the use of the SBRT to the oligometastatic patients in the CRPC setting with PSMA PET positivity. And I was a little bit curious about how the utilization of SBRT might fit into this type of protocol. Is it allowed, is it excluded? How do you manage the SBRT in a patient who might have oligometastatic disease?

Fred Saad: Yeah, there are so many unanswered questions. This one is not allowing SBRT because obviously, we want to see what the lutetium is able to accomplish on its own. And the study that you're mentioning had to have disease on conventional imaging that was positive. That was in patients with metastatic CRPC first line getting enzalutamide plus or minus metastasis-directed therapy. And what we saw was that we significantly delayed RPFS, and the study was relatively small, but the trend towards an overall survival was seen. So very exploratory in a first line, but really MCRPC, so a later stage. But your question is very pertinent. I mean, in PSMA-positive disease, what is the value of metastasis-directed therapy? Here we are addressing that, but with a more novel approach to metastasis-directed therapy where we're hitting it with lutetium rather than with external beam radiation.

Oliver Sartor: Got it, yeah. Thank you for the clarification. And I'd forgotten about the other one requiring the conventional imaging. By the way, it's a very impressive study, and thank you for your leadership on that. Another question, Fred, we are living in the era where a lot of patients will receive an ARPI during initial hormone-sensitive disease, or perhaps in a STAMPEDE type setting where it may be lymph node positive in the pelvis and then get a couple of years of an ARPI. How do you manage those type of patients? These patients had a prior ARPI, a little bit distinct from those with just prior ADT alone.

Fred Saad: Right. Yeah, and you're right, that is a growing population. So we amended the protocol to now allow prior ARPI as long as it was discontinued quite some time before coming into the study because we really want to see the efficacy of lutetium with or without an ARPI. The STAMPEDE type population with very high risk localized that would've gotten two years of abiraterone and then became non-metastatic CRPC because of ADT added would be eligible for this study. But it's not an easy study to do, but it's I think, an important proof of principle of what lutetium can do in the absence of an ARPI is very understudied. And these are in patients not yet resistant to an ARPI.

Oliver Sartor: No, no, I think it's very interesting, Fred, and I think we'll be learning a great deal from this and the other studies in this space. It's almost like a checkerboard and we're beginning to fill in individual pieces of the checkerboard and examining lutetium. We had the lunar trial, but of course, that was in the castration-sensitive setting with the PSMA-DC trial. But that is a conventional imaging negative, going to an MFS endpoint, trying to get an FDA approval, so all sorts of little nuances here. Is the trial underway now, Fred? And if so-

Fred Saad: The trial is underway and the recruitment is picking up. We've got 13 countries involved because it's [inaudible 00:08:02] but we think that it's going to pick up quite quickly now with the amendments that we've brought in, because clearly these non-metastatic CRPC, the use of PSMA is more and more widespread so we can't really call them non-metastatic, but what do we do with these micrometastatic patients is a question. Do we need an ARPI in all of those patients? And what can an RLT bring to these patients is going to be quite, I think, interesting. We won't answer all the questions, but like you say, we'll learn. Right now we're giving the conventional six cycles of lutetium. That also is something that we're going to have to explore as to whether we actually need six cycles or not. And we'll look at how quickly PSA declines and how quickly PSMA shuts off and see if maybe less is required for these patients that haven't progressed on the ARPI and are still micrometastatic.

Oliver Sartor: Do you allow what we would call adaptive dosing, so if somebody gets into a complete remission that then there's the option to be able to hold the dose for a period of time?

Fred Saad: For now, the trial is designed on the standard dosing, but obviously these are questions that both you and I are involved in other trials where that question keeps coming up, how much do we actually need? And this is a little bit different than the hormone-sensitive setting. These patients have already progressed on an ADT, so it's more aggressive disease and the likelihood of progressing to metastatic disease is quite high. It's basically over 60% within three years are going to progress to a metastatic state. So if we introduce this therapy early, can we delay the addition of other therapies, is really what we want to explore. But the adaptive dosing, we have regular meetings to see, should we modify the design? And these are questions that are going to be hopefully discussed.

Oliver Sartor: One of the other questions that comes up, Fred, is the type of imaging, the frequency of imaging. And I wonder if you might be able to help our listeners understand, are you going to be using PSMA-PET imaging in a repetitive fashion? Is it part of the endpoints? Is it part of the assessment tools, part of the response criteria? Tell us about the molecular imaging and the conventional imaging and how they interact.

Fred Saad: Right. Right now it's really PSA-based response and the definition of progressing to metastatic disease is still based on the FDA almost obligation to be using conventional imaging. We obviously will explore the utility of PSMA-based, but it's still the same definitions as we used with the classical trials that we did with the non-metastatic CRPC until visible metastasis on conventional imaging. But we will have an opportunity to explore what is going on with molecular imaging until they reach that state. But what we don't want is to hurt the trial because obviously, if you do a PSMA and you see something that is not necessarily clinically significant, would it change the dynamics? I think we'll be able to try to answer several questions with this very small study.

Oliver Sartor: One more question, Fred, just a clarification on that last point. Obviously, you'll have the molecular imaging in the beginning. Will you have repeated molecular imaging during the course of the lutetium therapy, or how will you manage that? Because if people wonder about, "Hey, what happens if the target disappears, should you continue the therapy," that'll be a question that'll come up in the analyses.

Fred Saad: Yeah, and it's an excellent point, but right now it's still based on regular conventional imaging until the appearance of metastatic disease on conventional imaging. But your point is very well taken. Should we include more, given the changing landscape since we actually started this trial? That's a discussion point.

Oliver Sartor: Fred, we're going to wrap up here in just a moment. Are there any final words, final thoughts you'd like to share with our listeners?

Fred Saad: Well, besides hoping that we can really make a difference in our patients' lives, I think we're moving in the right direction. And what we hope is that we can one day say we take these patients early enough, hit them hard enough that we can hope to stop treatment altogether. We really need to go towards a de-escalation route, and maybe by addressing the disease in a window of opportunity where we might actually be able to kill off the disease, what I hope is we can stop all treatment, including ADT in many of these men, rather than keeping them in that castrate state for the rest of their lives. Very exciting and I hope we continue working together for many more years to reach that point in prostate cancer.

Oliver Sartor: Fred, I love your goal, and it's one that I share. We treat a lot of patients with prostate cancer, we've been doing it for years, and I would love for the opportunity to be able to move some of these more effective therapies earlier, hit them hard and then give a break so people can be off therapy, potentially enjoying life without castration. I share your goals, I applaud your goals. With that, we're going to wrap it up. Fred Saad from University of Montreal leading in another important trial with PSMACare. Thank you, Fred, for being with us today.

Fred Saad: Thanks, Oliver. A pleasure.