Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, a good friend and colleague, Dr. Michael Morris, who's the Clinical Director of the GU Medical Oncology Service and the Prostate Cancer Section Head at Memorial Sloan Kettering. Thank you so much for being here with me today, Dr. Morris.

Michael Morris: Oh, thank you so much for having me, Alicia. I really appreciate it. It's always good to talk to UroToday.

Alicia Morgans:  Well, it is always good to talk to you, and I wanted to really talk with you about some ESMO 2021 updates on lutetium-PSMA-617, because certainly, this is another meeting where it was highlighted. Can you share with us a little bit about the VISION trials quality of life updated data that we heard from Karim Fizazi, and of course, your team at ESMO 2021?

Michael Morris: Sure thing. If you recall at ASCO, we fo focused on the survival and the RPFs data, which were the two primary endpoints of VISION, and so in the primary clinical goals of all treatment of improving how patients feel or function or survive, survive and RPFs were presented at ASCO. At ESMO, the feel and function endpoints were presented. And so, really, there were three pieces of data that were presented at ESMO by Dr. Fizazi.

The first was the symptomatic skeletal event rate. This had actually been published in the New England Journal of Medicine paper, which showed a risk reduction to the time to an SSE, being of it on an order of 50%, or the hazard ratio of 0.5. And then again, in terms of feel and functionality, at ESMO, Dr. Fizazi presented the time to worsening QOL as assessed by the FACT-P, which showed a hazard ratio of 0.46 in favor of treatment with lutetium and the standard of care and the BPI short form, the BPI-SF, time to worsening pain, favored treatment with lutetium in addition to the standard of care, as opposed to a standard of care alone, with a hazard ratio of pull 0.45.

So I think that ASCO and ESMO form very complementary data sets, where the advantages for this very advanced treatment population in favor of receiving lutetium plus a standard of care, as defined in the protocol, anything other than chemotherapy or radium or immunotherapy, favors lutetium for survival, time to radiographic progression or death, time to worsening quality of life, time to worsening pain, and time to a symptomatic skeletal event, all favor the use of lutetium. That was an extension of a previously reported and now completed phase 3 study. Those data now are under review by the FDA, and so I think we all, as a community, eagerly await the results of that review, so that we can hopefully incorporate lutetium in as a standard of care to the armamentarium of the post-chemotherapy-treated metastatic CRPC population.

What also was presented, and I had the privilege of presenting on behalf of the other investigators, was the PSMA fore population clinical trial, and that is a phase 3 study looking at the patient population that just precedes VISION in terms of place on the timeline of metastatic CRPC. And that's post abiraterone, enzalutamide, or apalutamide or whatever androgen receptor pathway inhibitor. So after treatment with an ARPI, but before treatment with chemotherapy in the chemotherapy naive metastatic CRPC population. That trial has a somewhat different design than the VISION trial. Instead of having two primary endpoints as VISION did with RPFs and OS, the primary endpoint of the PSMA 4 trial is just RPFs alone. The reason for that is that this trial does allow a crossover, which VISION did not, at radiographic progression.

In PSMA fore, it will take the pre-chemotherapy metastatic CRPC population and randomize them to either lutetium or to the ARPI that they did not previously receive. So, generally speaking, that would be Abi to Enza or Apa, or Apa or Enza to Abi, basically mirroring the same design that the PROfound trial had in the phase 3 study for olaparib. So this patient population will have an opportunity to cross over to who receive lutetium if they progress. As such, OS probably won't have a particularly meaningful readout because it's really just a question of delayed therapy that is lutetium now versus lutetium at progression. RPFs is the primary endpoint, of course. OS, PSA changes, time to second progression, time to SSE, and a host of correlatives are also endpoints in this. But those are the key design features of PSMA 4, and this is the then second study in metastatic CRPC for lutetium.

And then also, there was a Trials in Progress poster for PSAA edition, that's in the castration-sensitive population. And of course, similar design to PSMA 4 with a crossover, but that's ADT plus an ARPI plus lutetium, versus ADT plus an ARPI alone. So it was a pretty busy meeting at ESMO for lutetium. A lot of things going on.

Alicia Morgans:  It is a busy meeting, but I really think, and commend you in the team, for giving us the opportunity to understand the activity of lutetium across the faces of disease, because these are all very distinct patient populations and we may see very different things. It's even possible in PSMA 4 that, that earlier initiation of lutetium may affect overall survival. And we've seen that in some other disease states that we can't make up for the time lost. So I think that will be very, very interesting. Would love to hear your comments on that control arm.

Michael Morris: I'm sure that we're touching on a pretty controversial area now in today's day and age on the control arm for both of those studies, but I think probably the most controversial would be PSMA 4, because for a PSMA addition, just getting an ARPI plus ADT would be considered a perfectly acceptable standard of care for newly treated disease. The controversy for the PSMA 4 study is, should those patients more appropriately be receiving chemotherapy?

In argument for chemotherapy would be that the CARD study would suggest that treatment with chemotherapy, such as cabazitaxel, yields superior cancer outcomes relative to a second-line ARPI. So why shouldn't patients get what is felt to be the most active control arm? Arguments against a chemotherapy control arm is, first of all, the CARD trial, all of those patients already had received chemotherapy. They had relapsed within a year of starting their initial ARPI, and as such, represent a very distinct slice of the metastatic CRPC population that is singularly high-risk. And we acknowledge that that high-risk population may not be well represented. In this clinical trial, we also have to recognize that if you look at most patients who have metastatic CRPC, most people do not get chemotherapy ever. One could argue that there are there weren't trials, like CARD to argue for that.

But I think there's more to that in the sense that, first of all, from a patient's perspective, if you ask most patients, whether they want chemotherapy, or let's say, another hormonal therapy or a drug like lutetium, most patients aren't raising their hand to volunteer for chemotherapy, and it has significant impacts on quality life and functionality, et cetera.

The second issue is that there are some patients, I think that we can all acknowledge, who would be poorly served with chemotherapy as second-line therapy. So let's say for example, you have a patient with a very limited distribution of disease, let's say one or two lesions. Their PSA is rising on upfront abiraterone or enzalutamide. Would you make the compelling argument to that patient, by having a few lesions, that they need to go onto docetaxel or cabazitaxel every 3 weeks? That's a different patient than let's say, a symptomatic man with a high disease burden who is rapidly progressing, as opposed to the person with a very limited amount of disease slowly progressing, many years on treatment with an ARPI, doing very well. Is really the next thing chemotherapy? Is that the most appropriate next therapy?

I think that painting the entire metastatic CRPC population with a single chemotherapy-oriented brush will overtreat a lot of patients and make them not necessarily happy people. And I see that your, your friend there completely agrees. He's raised his hand in agreement. So I think that it's certainly a topic that's worthy of discussion, but not all CRPC after progression with abiraterone, warrants chemotherapy, and both clinicians voting with their feet would say so, because most patients don't receive that and most patients wouldn't want that.

Alicia Morgans:  I would actually add to that, that patients vote with their feet too, and I think that patients are going to really appreciate the opportunity to see if a second AR-targeted agent may be beneficial to them and they also know that they're going to be getting lutetium if that progression, when that progression occurs. So I really appreciate you talking through that, because of all designs, this is an extremely responsible way, I think, for you to allow patients to have that opportunity for that second AR-targeted agent, which we know may or may not be effective. But they are all already in the pipeline then to get that treatment with lutetium, and I think that's actually quite a powerful backup for them. And so, commend you actually on this design.

Michael Morris: I think it's also worth remembering, this is not our first debate about this in the field. When docetaxel was originally approved and all we had for all metastatic CRPC was docetaxel, we needed to do some trials which were pre docetaxel. That's how the whole pre versus post-docetaxel distinction, from a regulatory standpoint, came into being. And there were those who said, "Oh my God, if you have a placebo-controlled pre-docetaxel," Take, for example, Cougar 301 or Cougar 302 or PREVAIL. Those had, essentially, nonactive control arms pre-docetaxel.

Now, there were some who said, "Oh, that's terrible. They should be getting docetaxel as the control arm," As though docetaxel or chemotherapy were some magical, fabulous therapy that actually prolonged life for more than just a median of 2 to 3 months. And that this was really denying people some terrific, active, highly sought after therapy. Let's not inflate chemotherapy to a status that it doesn't belong in these pre-chemotherapy studies, and just as we shouldn't have, and I don't think most of us did, in those other pre-chemotherapy studies a generation ago. There's a place in the realm of metastatic CRPC where we're looking to alternatives to chemotherapy and control arms. And how that then distributes in practice and standard of care, we'll see.

Alicia Morgans:  I agree. I think at the end of the day, we want to get as many treatments to our patients as they can tolerate, always sharing their preferences in that decision making process as well. So again, kudos to you and the team for really giving us an understanding of where lutetium fits into our paradigm in a way that helps us and will help us use this drug most effectively for years to come. If you had to make a final comment on this, what would that be?

Michael Morris::  Well, I think that we're going to encounter these discussions in many different contexts, because not only do we have lutetium, but we have many radiopharmaceuticals and radioligands that are coming online. We are going to want to put them in a variety of clinical contexts in which there is an uncertain standard of care. I would encourage all my colleagues not to be particularly dogmatic where there really isn't a standard of care, creating an artificial one. Because this will come up in the pre-metastatic situation as well, it's going to come up in the context of high-risk localized disease if we can move the field there.

There are going to be many decisions to be made and there will be some designs that are more controversial than others, but I think it's a pretty exciting time as a field to have so many drugs moving into prostate cancer in this family, in new combinations and new sequences, and it's really a terrific time for patients to participate in these and to see these drugs move into standards of care that will ultimately help them at a variety of points in the disease.

Alicia Morgans: Wonderful. Well, thank you so much for keeping the momentum going in all of this work and for keeping all of us updated on where things are going and certainly what we understand and know about lutetium-PSMA-617 now in terms of our disease control endpoints and also our quality of life endpoints. We really appreciate your time and your expertise.

Michael Morris: It's my pleasure. Thank you for having me and thank you to UroToday, as well.