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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a good friend and colleague, Dr. Michael Morris, who is the Prostate Cancer Section Head at Memorial Sloan Kettering in New York City. Thank you so much for being here today to talk with me about the VISION presentation that you have given at this year's ASCO. Thank you, Dr. Morris.

Michael Morris: Thank you very much for having me, Alicia. It's a pleasure to be with you.

Alicia Morgans: Well, it is a pleasure to talk about this data. I think we are all so excited to hear about this. Can you tell us a little bit about a review of the VISION trial's schema so that we can put all those results into context?

Michael Morris: Sure, of course. So, first of all, in terms of what this drug is, before we go into the schema of the trial, it is a PSMA directed radioligand therapy. PSMA has long been a very promising target for both imaging and for therapy and prostate cancer, it was cloned in 1993. So it has been a long time coming and there have been many different studies looking at using PSMA as a therapeutic target. The molecule that is used in the VISION study is called PSMA-617, and it's a small molecule that binds to the external domain of PSMA. And it's carrying a payload of a beta emitter called lutetium-177. So altogether we say it is, lutetium-177 PSMA-617. I know that's a bit of a mouthful, but you get used to it after saying it enough times.

This trial was a randomized prospective phase 3 study of men with metastatic CRPC, who had completed at least one therapy with an androgen receptor pathway inhibitor, such as abiraterone or enzalutamide or apalutamide, for their castration-resistant metastatic disease, and they also have had to have completed one or two taxane regimens. They also needed to have a PSMA positive PET scan, illuminating that they had the target on their disease, and their physicians needed to feel that any further chemotherapy for them was inappropriate.

So you can tell from that list, these are patients who have been extensively pretreated, having completed an ARPI as well as chemotherapy, and they had to have a PSMA positive PET scan. Their physician would then assign them to some appropriate standard of care, and that had to exclude chemotherapy, immunotherapy, and radium-223, or other investigational drugs because we didn't have safety data on the combination with lutetium PSMA. And then they were randomized to a 2 to 1 basis to either receiving that standard of care with or without, the lutetium PSMA-617. And there were two primary endpoints, one was radiographic progression-free survival, and the other was overall survival, and the study was designed so that if either or both of those are positive, then the study would be considered to be a success.

Alicia Morgans: Well, very important. And thank you for clarifying exactly how those patients were chosen and for really clarifying that in the treatment arm with the lutetium, these patients received that combination of best supportive care plus lutetium, which really helped to dictate what the control arm was going to be because we had to have that safety data-

Michael Morris: Yes indeed.

Alicia Morgans: What was the final finding? Of course, we've all heard the press release and many of us have probably seen the ASCO presentation, but what was your primary result?

Michael Morris: Sure. Let's talk about overall survival first. So the hazard ratio was 0.62, which in plain terms meant that the risk of dying was reduced by 40% in favor of receiving the combination of the standard of care, plus lutetium PSMA. So, a 38% reduction in the risk of dying, a p-value of 0.001 with an absolute improvement in the median overall survival from 11.3 months to 15.3 months. So a four-month improvement in median overall survival in terms of absolute improvement and a 38% risk reduction for dying, if you look at the relative risk across the population. For radiographic progression-free survival, which is the time from randomization to either radiographic progression or death, the hazard ratio was 0.4. So a 60% improvement in the likelihood of remaining free of radiographic progression or death, with an improvement in terms of median time to RPFS from 3.4 months to 8.7 months, and with a p-value of less than 0.001.

So whether you look at the primary endpoint of OS, or the primary endpoint of RPFS, it was still a positive trial and that positivity also played itself through the secondary endpoints of achieving a PSA decline of either 50% or 80%. So in favor of lutetium of 50% decline was seen in 46% of the patients in the lutetium arm, and 7% in the control arm, and 80% decline in 33% of the patients who received lutetium and in 2% of the patients who received the standard of care alone. And then finally, in terms of responses, a 9% complete response versus a 0% complete response rate in favor of lutetium and a partial response rate, 41.8% of those patients who received the lutetium had a PR and 3% who received just the standard of care, had a partial response. So PSA imaging, RPFS, and OS all hit in favor of receiving lutetium PSMA.

Alicia Morgans: So, that's fascinating. And let's talk a little bit about that. So first in terms of the PRs and CRs, was this by traditional RECIST and bone scan? Was this by PSMA scans? How did you and the team actually quantify those responses?

Michael Morris: So for RPFS, it was by the traditional prostate cancer working group 3 criteria, so, that follows the traditional 2 + 2 rule set out in that document. I should say, that these patients were not restricted to the patient population with strictly measurable disease. These were typical prostate cancer patients, where the majority did not have measurable disease, the majority had the bone-only disease, and that is important to recognize because that is specifically the patient population of the prostate cancer working group 3 had in mind, and also speaks to the broad generalized ability of these data, it's not to some select patient population who strictly have measurable disease.

But the CRs and the PRs are only those patients who did have soft tissue measurable disease or a soft tissue component of bone disease, I suppose, but who are RECIST-evaluable and that is a subset of the patients, right? So, that is not the full patient population. The measurable disease data is the subset who did have measurable disease and in the end, that was 184 patients who received the lutetium who had measurable disease, and 64 who received the standard of care alone.

Alicia Morgans: Great. Can you tell us a little bit about what the standard of care was, or just some impression of percentages of patients? Because I think as you mentioned, these patients couldn't get chemotherapy, radium, or immunotherapy. So what were they getting?

Michael Morris: Most of these patients got further androgen receptor-targeted therapies. So if they had enza, then they received abi. If they had had abi originally, then we received enza. They could also receive bicalutamide, they could also receive nilutamide. And if you look at the general patient population, just under half, 47% of patients got either enzalutamide, bicalutamide, apalutamide, darolutamide, or nilutamide. About a third of those patients who are on the lutetium arm, got that. And then if you look at the other options that patients got, some got steroids, some got denosumab only, or other bone-directed therapies only.

Patients could also get just palliative radiation and supportive care as well. So I think that it's a pretty typical, non-chemotherapeutic regimen of standards of care. And do remember though, that first of all, as part of the eligibility, these patients were felt to be inappropriate for further chemotherapy, and second, clinicians were encouraged, if they felt that calculus had changed and they did want their patients to get more chemotherapy, they were encouraged to pull the patient off the study and give the patient what they needed.

Alicia Morgans: Absolutely. And I wanted to make sure that we clarified that because I think as VISION was enrolling, there were patients who I think in my clinical practice at least, I thought might ultimately be better served with chemotherapy. And so we actually did pull those patients off and put them in that direction, and some patients made that statement themselves. But, there were some challenges in the initial enrollment because although these were heavily pretreated patients, which also makes these results that much more encouraging and exciting, there were heterogeneous control options used, and patients often had a preference and thought to themselves, "Hey, I think lutetium is going to work," and would try, maybe to think about trying to get onto that treatment arm, not that they were able to.

But, there were patients who were so eager and so interested. So can you speak a little bit about some of the challenges, maybe in doing a clinical trial like this with a drug that is so exciting and has some preliminary data at least, from places like Germany, where that was a real challenge that you faced and still this trial was incredibly positive?

Michael Morris: Yeah, it was an interesting experience. So you're absolutely right, Alicia, that going into this study, there was already the start of the loss of equipoise because of the German and Australian data that was coming out, that really, that this was a pretty powerful agent in terms of its anti-tumor effects. Of course, in many ways that equipoise was prematurely fading because there was no data, zero data, that this agent had clinical benefits like life prolongation, or even delaying radiographic progression. So I think that's always a dilemma where you are in that gray zone where there is promising early data, but non-definitive data in terms of clinical benefit, and yet you want to do the trial, in which you demonstrate clinical benefit, and how do you work that out?

When we first opened this study, which opened in June of 2018, it was really clear that something was not going well in terms of the study's allocation of patients. So over 50% of the patients who were assigned to the standard of care alone arm, dropped out. And I think that was a combination of factors, but some investigator related, some patient-related, but what happened was we stopped the study briefly, re-conferred with the FDA, and in a sort of consensus plan, there was a period of re-education of the investigators on the intent of the protocol, strengthening of the nuclear medicine and medical oncology relationships. So that, for example, if a patient were allocated to the standard of care alone arm, and was not assigned to the lutetium containing arm, that patient would still get really good medical oncology care and would be able to participate in this study. And so with that process of re-education, the dropout rate steeply declined so that when the trial reopened to accrual in March of 2019, that dropout rate went from 56% to 16% in the standard of care arm.

And I think that it really does speak first to the real need for clinical care, to be joint, with both nuclear medicine, and if it's a radiation oncologist giving this treatment, then radiation oncology with medical oncology, because it is with the systemic therapies that the medical oncologist would ordinarily be using. And it's really important to have that joint partnership to take care of the patient. But it's also really important to recognize that when you are doing nuclear medicine studies that involve patients who are this sick and involve also a standard of care with systemic therapy, that you need to go in with those tight connections as co-investigators at each site. So there are many lessons, both in terms of patient care and protocol conduct that come about out of that experience.

I would say though, that it's also important to recognize the number of patients who actually received therapy after completing the trial, which would have been prohibitive during the trial. So for example, you gave the example of a patient that you had where you gave them chemotherapy afterward, but that was actually the minority of patients. So, it was around 20% of patients who went on to get chemotherapy after the protocol was completed. It was really the minority of patients who crossed over to get some form of radiotherapeutic after the study. So in the end, it didn't really look like there were that many patients who were inappropriately put on this study, who then were randomized to the control arm, and then desperately seeking some form of therapy precluded by the trial.

Alicia Morgans: I think that this was certainly a smart design and a design that needed to happen. And I'm glad that we were able to look at lutetium in combination with some of these other therapies in a larger scale than certainly just safety finding studies, phase one's combination studies. So I think that this has informed our field. I think that we are all incredibly excited and looking forward to the opportunity to use lutetium in the standard of care when that time comes. And as we wrap up, what would your message be to listeners who are excited and really congratulate you on this fantastic work for you and the team on the VISION Trial?

Michael Morris: I think it's a real win-win for patients. And that is the most important thing. This trial was in patients who had really very few viable treatment options remaining to them. And this shows that this new drug class for prostate cancer, radio-targeted, radioligand therapy, opens up a real doorway, not only for these patients who have completed an androgen receptor pathway inhibitor, plus chemotherapy, but it opens up the doorway also to future studies, looking at this therapy earlier in the disease. And we've generally found that when we move a drug from this late population to an earlier population, that those clinical benefits can be amplified and opens the door to combination studies so that we will be able to see how to further optimize this therapy.

And then finally, this is the first trial in prostate cancer in which a PET scan has been used to identify the target of the therapy, and then have that therapy be given to that specific population and result in a survival benefit. So conceptually, the era of theranostics in prostate cancer opens up with this trial. So we really have many different wins here, a win for a drug, a win for a drug class, a win for new opportunities to begin to build evidence for clinical benefit, and a win for a new approach in prostate cancer, all of which speak from a patient perspective, as new possibilities now unfolding with this study that is very promising as we look forward to the future.

Alicia Morgans: I completely agree. And I look forward to the opportunity to continue the multidisciplinary collaboration, to get this treatment to patients. And thank you so much for taking the time. And again, congratulations to you and your team. This is a bright day for men with prostate cancer, and we appreciate your efforts.

Michael Morris: Thank you very much, Alicia, for this opportunity to present these data and get them out there to both clinicians, the patients, and their families.