Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm here with UroToday at the U.S. Prostate Cancer Consensus Conference, third annual, in Colorado Springs. Here with one of the organizers, Alan Bryce. Alan, I'm going to introduce you as Professor of Oncology at City of Hope.

Alan Bryce: Yes.

Oliver Sartor: Based in Arizona. That may confuse people. Could you give a little bit of color to that comment just so people can understand where you are and what you're doing?

Alan Bryce: Absolutely. So at City of Hope, a number of years ago, we really decided that it was time to build out a national cancer presence. As most people know, City of Hope is founded in Southern California and Duarte and has really been focused there for the first 110 years of its history.

But then several years ago, we came to Arizona to Phoenix and brought on TGEN, the Translational Genomics Research Institute, where a lot of the early genomics work has been done, where I've done a lot of my early work, in fact. And then City of Hope said it's time to expand the clinical footprint as well.

So three years ago we bought a hospital in Goodyear, Arizona, and then City of Hope asked me to come over and help build that practice. So I moved over to City of Hope, Arizona, where now I continue my prostate cancer practice, and we're building a new academic cancer center for the state of Arizona.

Oliver Sartor: Nice. Thank you for the explanation, because I think it has confused a few people along the way.

Scott Tagawa's a little bit easier. Professor Scott Tagawa from Cornell. Been there long time, Scott, and you're a professor in both medicine and urology, a little bit unique. Welcome, Scott.

Scott Tagawa: Thank you.

Oliver Sartor: So we're going to be talking about one of my favorite topics, and that's the use of PSMA-targeted therapy, and both of you have plenty of experience. You go way back with the antibodies, but I think we're probably going to concentrate on the small molecule. And why don't we restrict our comments to PSMA-617 lutetium-177, because we could talk about various iterations of these isotopes and molecules, but we're going to stick to those that are FDA approved.

And there was an important trial called a VISION trial, that was the first one to lead to the approval. And in order to be eligible for the VISION trial, you had to have A, PSMA, Positive Metastatic Disease [inaudible 00:02:31]. You had to have prior treatment with a taxane, and an ARPI, and obviously ADT. So you must have progressed with metastatic CRPC after chemotherapy, ARPI, kind of at the last stage.

And there's another trial that's also relevant to our discussion called PSMAfore. And PSMAfore again used the PSMA-617 Lutetium, but it did not require the pre-treatment with the chemotherapy. It's after ADT and an ARPI, again with PSMA-PET positive metastatic disease. So, those are the two studies we're going to focus on.
And, Alan, you might have beliefs or preferences about whether or not we ought to be giving the PSMA Lutetium a little bit later, a little bit earlier. I wonder if you might articulate a position, one or the other, and then whichever one you take will give Scott the other one. There we go.

Alan Bryce: All right, so I get to pick which side I'll be on. Well, I'll tell you, I am giving PSMA Lutetium prior to Docetaxel based on the PSMAfore data. So I'm very comfortable with that.

With the FDA approval, and we can get into why there might be controversy with the data, but even the data being as it is, I'm very comfortable with the idea that it's appropriate to give Lutetium prior to docetaxel.

Oliver Sartor: Well, what if this idea that maybe you're going to give the Lutetium, and then your later courses of therapy like docetaxel, Cabazitaxel may be compromised? Is that a concern to you?

Alan Bryce: So it is absolutely always part of our thought process. Every new drug that comes to market, every new indication that we have, will impact every subsequent therapy. So this question isn't unique to PSMA Lutetium, it's a consistent question we have to think about with anything.

And I think as an oncologist, our responsibility is to think about the entire treatment journey, not just one point in time. So, I always tell my patients when I'm thinking about their treatment from the first day I meet them, I'm not just thinking about what do we need to do now, but I am thinking about from beginning to end, how does every choice impact every subsequent choice? Because really the goal is to get the best possible totality of care, with the best outcomes, the least toxicity, et cetera. So it's absolutely appropriate to ask the question of what happens next.

But the answer, the technical answer, in this and every one of these scenarios, is we don't know. We can only surmise. There's no question at all. No matter what treatment you're talking about, you get diminishing returns with each line of therapy. So with any one of our therapies, when you give it later, you get less benefit out of that line than you would've with the same drug earlier.

But as I said, that's not really the question. The question is, again, the totality of all the drugs together, do you get a better outcome or not? And that's a question we don't have an absolute answer to. We can only speculate.

Oliver Sartor: Now, Scott, you can take a different, or maybe in a similar opinion, but we're having a discussion, not necessarily debate. So, Scott, how would you view this scenario, pre-chemo, post-chemo, and in your practice, do you have a particular preference?

Scott Tagawa: I think most of our audience will know, but just say it explicitly, in the initial study, you know very well, designed mirroring ALSYMPCA after pretty much everything else. And we thought we had a good therapy, but we needed to get it to the masses, and get it FDA approved, and therefore best standard of care defined by the protocol, with or without Lutetium PSMA-617, and with the alternative primary endpoints, RPFS, but in addition OS. So that's really cemented that, and we have overall survival for this particular drug, and that's great to have it. No crossover in that particular study.

What I like about this approach, which is not only Lutetium PSMA-617, that could be other PSMA targets, other PSMA agents and other targets, is the theranostic approach. So one aspect which you mentioned actually I think you mentioned the first criteria is the PSMA positivity by imaging.

And there is the VISION criteria, and there's other criteria there. But in the setting, forget the pre or post-docetaxel. In the setting where there's more choices, then I think we want to think about the entire picture both in terms of potential toxicity, as well as what do we think that individual benefit for response is going to be, or for a time-to-event endpoint like survival.

So every single analysis that has been done really points towards one element of that is the quality of the PSMA imaging going in, associating with outcome. So very bright and homogeneous, particularly brighter than the parotids, we can look at SUV mean and max, things like that, which are I think can be useful, especially for a study harder with a patient. But overall, the brighter and the more homogeneous it is, the higher the likelihood that patient is going to respond and therefore I would tend to want to use it earlier if all the other parameters are met.

Oliver Sartor: So you're looking at that scan, and looking at the characteristics, not only the SUV in a visual way, but also the degree of homogeneity heterogeneity.
What about location? What if you have a liver met, or you've got a low PSMA SUV liver met? Does that drive you one way or another in your thinking?

Scott Tagawa: So not surprisingly, in the setting of liver metastasis, this drug works less well, like all the other drugs, because that's a poor prognostic sign. Actually, what I tell people, the first one of my fellows to surpass me in the field, Misha Beltran, has published that... Another one who has done it, too.

Has shown that the liver tends to be a little bit less as an organ with less PSMA, but occasionally it is quite bright. So it's not that there can't be a response. In fact there was a radiographic progression for survival advantage in the VISION trial with that versus just standard of care, but I do think twice about that.

So, particularly in a chemo-naive setting, for me it has to be really, really bright and homogeneous, particularly in the liver, and/or the patient is really a poor candidate for chemotherapy that does exist, so those are the typical combinations that I will think about.

We do know that there are organs that can be more important than others. So for instance, bone with radium with their three-centimeter lymph node along treating most of the tumor in the bone, we can ignore that, although we can do combination therapy. So it stands the reason that there can be some heterogeneity and still have some success with PSMA-targeted therapy, but liver is one of the most dominant organs in terms of prognosis.

So it's an area that I would like to not treat. So earlier I'm thinking of some of the other options that I trust a little bit more in the liver, not that there can't be responses, and I'll use PSMA-PET late if there's heterogeneity, than what I'm thinking about, let's just say the scenario that there's five lesions, four really bright one's dim, I'm watching that and maybe coming in with some therapies for that specific lesion.

Oliver Sartor: Like an SBRT type?

Scott Tagawa: Correct.

Oliver Sartor: I've worried a little bit that I'm oversimplifying the debate, and I'm with somebody who knows a lot about PARP inhibitors when I look at Alan. And I wonder just briefly, we've given this chemo versus Lutetium, and we are oversimplifying.

Alan, let me hear that from your perspective and how you look at all the possibilities, not just these two, when evaluating a patient.

Alan Bryce: Absolutely. So I think playing off of what Scott was saying, and again, getting back to this concept of thinking about the totality of care and then how do we think about what's going on with the cancer and deciding where does chemo come in, where does radioligand therapy come in? Et cetera.

We know we talk about this all the time, the cancer is constantly evolving. And we're talking about, essentially, an organism where we come in, we're applying natural selection, and we're watching Darwinian evolution happen in real time.

Oliver Sartor: Agree.

Alan Bryce: This is the dynamic process happening in the cancer within our patients.

So a few points about why we choose one drug or the other, or how I think through the logic. One of the issues is certain drugs will cease to be effective at different time points along the course. For PSMA-targeted therapy, the key criteria is you have to be able to localize the drug to the site based upon PSMA expression.

So knowing that PSMA expression is both heterogeneous and diminishing over time, keeping in mind this concept that PSMA expression is highest early in the CRPC course and more or less absent once we get to anaplastic disease, small-cell disease, whatnot. There's the possibility with a given patient that we lose our chance to use this effective therapy if we wait too long.

The other side of that is when patients are getting towards the far end of the anaplastic spectrum, neuroendocrine, small cell, whichever path we end up on, then what we're reaching for is chemo.

So what I'm saying is you think about the fact that chemo utility is maintained a bit longer, I would argue, than Lutetium utility, and this is one of the reasons why I think if I have to pick, in a scenario where there's no absolute answer of which one is better, then I'm thinking I feel like I have a better chance at getting efficacy from both, if I use my Lutetium a little earlier in my chemo a little later.

Now, we can design specific scenarios where we might give a different answer, and one of them is this scenario where you have your most problematic lesion, maybe that liver metastasis, some other visceral metastasis, that has very low expression.

And as you just talked about, if we have a lesion that can be approached with focal therapy somehow, radiation or otherwise, then we feel like, okay, we're addressing that. That's okay. But if you have an alternative scenario where there's multiple, non-AVID lesions in areas where focal therapy just isn't going to be the answer, that's when I'm going to tilt away from Pluvicto and tilt towards chemo.

Now the other piece that comes into that is genomics, and I think we still have a lot of work to do to further refine, really saying, "When should we expect resistance to radioligand therapy based on genomic signatures?" What I would posit to you, we won't see surprises there. We know what aggressive disease looks like once you start getting multiple loss of tumor suppressors, et cetera, response to almost everything drops.

So I think we'll get more sophisticated in our patient selection. And then the last question of, "Well, where does PARP generally fit in?" I am largely doing the PARP before the Pluvicto for the BRCA-mutated patient. If someone told me they do the opposite, I wouldn't tell them they're wrong. It's a completely debatable point. Again, it's how I think about tumor evolution. Which modality are we likely to lose utility from first? And how do I get a better cumulative response is how I'm thinking about it. But again, it's a totally point, which is the point of this conference to have these debates.

Oliver Sartor: One of the things that's really a pleasure is to be able to hear your expert opinion. You've thought it through, you're thinking about the patient journey. And, Scott, I know you as well, but it's really a pleasure to talk to you guys, because you know what you're talking about. We don't have that much more time. But I want to introduce a complicating factor.

It was a press release that came out, actually during ASCO, that says, "Oh my goodness, if you take an ADT and ARPI in the hormone-sensitive setting, and they're PSMA-PET positive, and now you randomize to receive the PSMA Lutetium in half the patients, those patients do better, at least as the primary endpoint of RPFS with an OS trend." So now we're talking about moving this PSMA Lutetium all the way up and we don't have a lot of time to discuss.

But, Scott, do you think that'll take off, or of course, we haven't seen the data yet, so it's not really fair to ask you what you think about the data because it hadn't been publicly presented. And then I want to hear Alan's perspective on the same.

Scott Tagawa: So this to me, I'm a little biased, but to me this makes a lot of scientific sense.

So as Alan mentioned, the hazard of having PSMA-low tumors is lower in the earlier settings. We have dual AR-targeted therapy that should operate with PSMA, and there's discussions about that, particularly when you're looking at imaging, and there's data that AR-targeted therapy can radiosensitize. So it really should make PSMA-617 lutetium-177 work better. So it's not surprising to me that the press release is what it is, with the primary endpoint of RPFS better.

What I expect to see, is the control arm is going to be better than any control arm in the prior studies, because it is a very effective control arm. We've used ARPI as a standard of care for many patients right now. I just expect it to be better, and we know it is to some degree, with lutetium-177 PSMA-617.

The trend for the OS is comforting, there's crossover. We don't know how much crossover there is. I expect it to be a little bit later crossover than with PSMAfore, because the control arm probably works better, but at least at the early snapshot, high-level press release doesn't look like patients are dying earlier with getting Lutetium earlier.

And then the overall general statement, I don't remember the exact wording, but no new significant safety signal. So that's also nice to know, because although today the follow-up is still not that long, this is going to be a very rich data set to follow patients five, even 10 years, because it's nice that we haven't seen very much in the way of late toxicity with this drug. But we also have been treating patients with hormone-resistant disease, and even earlier PSMAfore, it's a two-year median survival. So that'll be very interesting to watch both the early and hopefully we'll see this soon, the early data come out, and then also to follow the patient's long-term.

Oliver Sartor: Thanks, Scott. Alan, any comments about this press release in the absence of data?

Alan Bryce: No, it is not surprising, you'd expect it to be positive. When you take a drug that's this effective, you move it into the hormone-sensitive setting... Since 2015 we've had a string of positive studies, so I expected this to be positive. We'll have to dig into the details when it comes out.

And of course what we won't have is the comparison of all the different combinations, that's just the reality of clinical trials. So it'll be a rich area for debate, then, for us to figure out with the multiple options any given patient will have: which one's the best for which patient? That's what I'll really dig into me. I like to slice and dice and really try to figure out a way to optimize for the individual patient.

So, not a surprise that this is a positive study, the specifics, the magnitude of benefit, we're looking forward to all the results coming out. I expect that this will be an option we'll be talking about for a long time to come, yet, once we've got the data.

Oliver Sartor: All right, thank you. A real pleasure. Scott, Alan, experts in prostate cancer, articulate, discussing the topic. Thank you.

Scott Tagawa: Thank you.

Alan Bryce: Thank you.