Read the Full Video Transcript

Charles Ryan: Hi, Chuck Ryan from the University of Minnesota here. I'm joined today by Dr. Oliver Sartor, Professor of Medicine and the Medical Director of The Tulane Cancer Center, and the C.E. and Bernadine Laborde Professor of Cancer Research at Tulane University in New Orleans. And Scott Tagawa, who is a Professor of Clinical Medicine and Clinical Urology and the Medical Director of the Genital Urinary Oncology Program at Weill Cornell Medicine in New York. These two are co-leading a pivotal clinical trial, which just launched, which integrates lutetium-177 with the standard of care therapy in the setting of metastatic castration-sensitive prostate cancer. Scott and Oliver, welcome, and thank you for joining us to talk about this study.

Scott Tagawa: Thanks so much for the invitation.

Charles Ryan: My first question is going to go to you, Scott, as PI of the study. This is a study that is being done internationally and so, tell us a little bit about the origin and the rationale for the addition of Lutetium earlier in the disease course.

Scott Tagawa: So several bits of background, I think most people are aware that multiple trials with different agents, either AR targeted agents or docetaxel when given earlier in i.e. non castrate or castration sensitive setting, have a much bigger impact on downstream overall survival compared to when they are used in the castration-resistant setting. So, that is one set of background. And we wanted to add to that lutetium PSMA 617, as I think most people are aware is a PSMA targeted beta-emitting radionuclide.  Without getting too much into the details, we now know that this works in the metastatic castration-resistant setting with an rPFS and overall survival benefit. And we wanted to move it up for several different reasons. One is that PSMA as a target, is there virtual all the time, the hazard for being there increases with less chance of AR so the more heavily pretreated the tumor is, I think the more likely it's going be to Lu-PSMA.

There is the mechanism of action[inaudible 00:02:12] we think of as radiation, which is more likely to have mutations such as p53 that may make a tumor less radio-sensitive. And then when given at the start or close to the start of ADT, and it will be really close to the start of adding an AR pathway inhibitor, we hope to accomplish a number of different factors. The two major ones being up-regulation of the PSMA targets as well as radiosensitization. So we really think that there will be synergy and we can get a much bigger bang for our buck when used upfront.

Charles Ryan: So you're not distinguishing between AR-targeted therapies in this study. It could be any of the available ones that are standard of care for castration-sensitive disease?

Scott Tagawa: Yeah. To add a commentary, any of them then really should be a standard of care because we know they haven't fully penetrated yet, but a drug such as 617 inhibitors and AR signaling inhibitors such as abi, apa, maybe daralutamide in the future, and enzalutamide.

Charles Ryan: So any of those plus ADT would be considered appropriate for the standard of care. And then tell us a little bit Scott, about the treatment arm. What do patients get? What's the timing of that and the dose, and how does that differ at all from the vVISION study that was just released?

Scott Tagawa: So the clear major difference is castration resistance versus castration sensitivity. The VISION study was an addition of an investigational arm to a standard of care. So in that way, it is similar where there is a background of ADT. Although this will be close to the start within 45 days, at least the initial findings consent and study procedure to leave within 45 days of starting ADT. And then they will add in a standard of care AR pathway inhibitor with, or without open-label lutetium PSMA-617.  The primary endpoint is rPFS, and this does unlike VISION, does include a crossover. So at radiographic progression, by the Prostate Cancer Working Group, and those that were on the control arm, as long as they are, we deemed them safe by standard criteria, they will be able to receive lutetium PSMA 617. That will be for castration-resistant disease, but much earlier than the VISION study.

Charles Ryan: Got it. So we'll get a sense of its efficacy in two different distinct states, castration-sensitive disease, as well as perhaps the chemotherapy-naive, for example, castration-resistant, prostate cancer patients. So, Oliver, you and I spoke recently, had a nice conversation about VISION, and one of the key criteria of VISION was that a PSMA PET scan was required to demonstrate essentially PSMA positivity. In the setting of hormone-sensitive diseases like this, how do you know whether PSMA, as expressed in our PSMA PET scans, is part of the criteria for entry into the study, and how do they figure into the outcome analysis?

Oliver Sartor: Yeah. So we are going to be looking at the PSMA scan upfront and just to ensure that there is evidence of PSMA positivity, relatively lenient criteria for trial entry.  In terms of the second question, Chuck, I'm not quite sure that we know how it's going to relate to the outcome because I think that is one of the questions we are going to be asking, so if I knew the answer to that question, I'm not sure I'd have to do the trial.  But now it is a PSMA selection, I think the vast majority are going to be having PSMA uptake, the metastatic lesions. And that's what we've come to learn from the variety of diagnostic scans that have been performed. But nevertheless, we do want to take a look at these outcomes as you suggested, but in terms of what we're going to find, I'm not 100% sure. So it will be interesting to find out.

Charles Ryan: Let me clarify my question, are PSMA PET scans used as an outcome measure in the clinical trial?

Oliver Sartor: No. And one of the things that we have to understand is that the FDA is going to be viewing things through the lens of traditional imaging. So if we look at rPFS, as determined, the FDA has not incorporated PSMA uptake as one of the endpoints that are a surrogate for subsequent clinical events, such as survival, that they believe is important. So it's going to be traditional imaging as the endpoint. Now there are all sorts of issues and questions that you can raise and what happens via PSMA positivity first and can you change therapies. All those issues are of course, subject to discussion, but traditional imaging will dictate the endpoints.

Charles Ryan: Okay. And the primary endpoints of the study are?

Oliver Sartor: It's rPFS.

Charles Ryan: Purely rPFS?

Oliver Sartor: Yeah, it's going to be rPFS, and Scott mentioned there is the crossover. Doing survival analyses in these types of patients, I mean, look at the SWOG study with TAK-700, we're talking about control groups of 70 months survival. So it's going to be tough to hit an OS endpoint with all the subsequent therapies that are available, particularly if there is a crossover. So I think the rPFS is very appropriate. And quite frankly, I think the FDA will react in a positive manner if they see this metastasis-free survival, this rPFS clearly hit, and it will need to be a magnitude, of course, it won't be one or two months that will make a difference. So it will have to be big.

Charles Ryan: Right. Maybe a conversation for another day, but we are doing quite well as a field I think in demonstrating the relationship between rPFS and OS, they are statistically correlated. And the question is whether or not rPFS over time will emerge as a surrogate for an improvement in survival, and whether it could become a repeated measure for FDA approvals in this setting or in others. So I'm hopeful that this may be one of those studies that will inform us a little bit on that front.

Scott, let me ask you, the VISION trial, very impressive results, likely to lead to a new standard of care in a group of patients who have had chemotherapy, who have had hormone therapy. And to be honest, their survival is just a lot shorter than what it's going to be in this group of patients.

And that brings up the question of long-term safety. Is there any concern that we should have, or what do we know, I should ask, about the long-term safety of patients who, like this receive lutetium 177 very early in their clinical course, who have a very long survival ahead of them?

Scott Tagawa: So the short answer and really the best answer is, we don't know. So this drug and similar drugs have been used in Germany and some other locations outside of clinical trials, even without ADT, but because they weren't [inaudible 00:09:25] prospecting to clinical trials, we do not really know anything about the long-term outcome. We do have a small subset of patients with quote long-term outcomes that have received similar drugs as part of a clinical trial. So Mike [Tung 00:09:41] at the 2021 ASCO had a poster presentation of long-term safety.  Long-term was defined as being alive and having the ability to assess safety more than six months after the last treatments, the median of 18 months. And as one might expect outside of still being on the main part of the trial, 100% had some AE, but then when we looked back and did our best to assess the relationship, it was a small minority that we thought might be related to their [inaudible 00:10:21] definite target range radionuclide [inaudible 00:10:22] therapy. Although, difficult to really tell.

Charles Ryan: We saw that same effect from the VISION study, didn't we Oliver where the AEs were greater in number in the lutetium arm than they were in the standard of care arm because people in the lutetium arm were living longer, were on therapy longer and had more opportunities to record AEs. That is a real issue in some of these long-term studies.

Oliver Sartor: Yeah. And just briefly commenting there. I mean, in the VISION, it was about 7.5 months versus two months. And that's a pretty substantial difference. And AEs do accumulate with time, particularly things like anemia that develops with progressive prostate cancer. So the etiology and relationship of AEs to the therapy, it's not always clear. And I think that will be the case here as well.

Charles Ryan: I just want to get a couple of clarifying points about the design of this trial that I think we haven't really touched on and that I would be eager to hear your comments, multiple stratification factors here, including volume of disease, which is important to point out because this is not a therapy for high volume disease, nor is it for low volume disease. All comers are eligible for this, and that's not being, that is not eligibility criteria for the study. And then treatment to the primary tumor is a stratification factor, which brings up two points. One is, will you allow treatment to the primary tumor while on study for a patient who presents with de novo metastatic disease, and then two, are we going to see an imbalance in people who have had primary therapy, then progress versus those who have de novo metastatic disease. Those two groups of patients have very different outcomes, Oliver.

Oliver Sartor: Yeah, you raised some interesting points. So first of all, in the volume of disease, I think prognostically we've seen, not only from the CHAARTED study but also from the STAMPEDE data sets that these two groups of patients have very distinct natural histories, and separating them out as stratification variables certainly makes sense. We've also worked with the STAMPEDE group, that [inaudible 00:12:27] radiation to the prostate is going to be something that is potentially important, and the hazard ratio is about 0.7. And those individuals treated with ADT in STAMPEDE, we actually do not have data with like an ADT abi. That analysis from STAMPEDE showed the effects of local therapy that were with ADT alone. That's the important thing. And now Scott would have to remind me, but I'm pretty sure given the fact that we have concomitant radiation, that the definitive radiation to the prostate when administered would be something we would encourage after the lutetium is given. And Scott correct me if I'm wrong, but that's my memory off the top of my head.

Scott Tagawa: Yeah, that's correct. So we allow treatment to the primary at the investigator discretion and that could be surgery, doesn't have to be radiation and that is investigator discretion independent of the volume of disease in the investigational arm, so there is some safety data from VISION and other studies of giving external beam during the course of therapy. But on this trial, if they are on the investigational arm i.e. getting lutetium PSMA-617 upfront, then they will get treatment to the primary following that.

Charles Ryan: Got it. So You could really envision a whole range of patients going on this trial, those with high volume multi metastatic disease with de novo metastatic disease, to those who have de novo oligometastatic disease who are really going to be treated almost with curative intent, perhaps by the addition of the radiation. But to be clear, you are not allowing radiation to the metastatic sites?

Scott Tagawa: Correct. Other than the palliative type of thing as we would in any study, but that generally would be a clinical progression sort of event.

Charles Ryan: Sure.

Oliver Sartor: Yeah, and Chuck, as you well know, the palliative type radiation would not have any effect, at least any known effect. It's the treatment of the primary in the low volume subset where we believe it could be prognostically important.

Charles Ryan: Yes. Well, great. And my understanding is this study has launched.  It has already accrued patients and it is launched internationally. Scott, can you tell us a little bit just about the structure and who is running the study.  It's a kind of unique partnership, I guess. And it's been a long time in development.

Scott Tagawa: Yeah. Those of us in the US cooperative system are well aware of the history that started with different versions of this study many years ago, that was carried forward, and as Novartis took it over. So within the United States, within the cooperative structure, or at least the same organizations, institutions are involved, the Alliance Foundation Trials organization and the RTOG Foundation are running the study with Novartis within the United States. And then Novartis is hiring or has hired a CRO to help them organize the trial in the rest of the world.

Charles Ryan: Excellent. So it's called AFT-53 in the United States or PSMAddition, also a name for it. And it's really a partnership between the US cooperative group system going back historically, as well as Novartis. I want to thank you both for your time tonight, which has been only a few short minutes, but really your time and dedication to the development of lutetium and radioligand therapy. This is a really exciting study in hormone-sensitive disease building on the really exciting work that was just presented and published from the VISION study. So thank you so much for joining us and, and we'll look forward to talking to you down the road as to the results of this important trial.

Oliver Sartor: Thank you, Chuck.

Scott Tagawa: Thanks much.