Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Dana Farber Cancer Institute in Boston. I'm excited to have here with me today, a good friend and colleague, Michael Morris, who is the prostate cancer section head and a GU medical oncologist at Memorial Sloan Kettering in New York, New York. Thank you so much for being here with us today, Morris.

Michael Morris: Thanks so much for having me, Alicia. It's a pleasure to be here.

Alicia Morgans: Wonderful. So we always love talking with you and today, I'm hoping to talk with you about the VISION Trial, which is such an exciting advance and hopefully will lead to an approval for treatment of men with metastatic castration-resistant prostate cancer. You and the team presented this information at ASCO 2021. Can you tell us a little bit about the study, and share with us what you found?

Michael Morris: Sure. This was a trial that was looking at men who had post androgen receptor pathway inhibitor therapy and post docetaxel or docetaxel and cabazitaxel chemotherapy, who were randomized to a protocol defined standard of care with or without lutetium-177-PSMA-617, which is in itself a PSMA directed small molecule with high affinity for PSMA that's radiolabeled with the beta emitter, lutetium-177. These men had a PSMA positive disease by virtue of a Gallium 68 PSMA scan. And the randomization, as I said, was two to one in favor of receiving lutetium plus the standard of care. The primary endpoint was twofold, first overall survival and then as well as an alternative endpoint radiographic progression free survival.

Alicia Morgans: Great. And can you tell us what exactly did you find as you treated men and just to be very clear, men received that best standard of care plus lutetium versus the best standard of care alone.

Michael Morris: Yes and we generally call it the protocol defined standard of care so we're not really sure what's the best standard of care for these men and the protocol itself did not allow as a standard of care chemotherapy, radium 223, immunotherapy, or other investigational agents. And there's a couple of reasons for that. First of all, the assignment of the standard of care was before randomization and we do not have safety data on chemotherapy or radium or the other agents with lutetium. So we needed to make sure that the randomization was safe and the standard of care was safe. And since we have no phase one data on those combinations, we disallowed that. In addition, all of these men were post-chemotherapy treated patients and around 40% of those men had received both cabazi and doce. So that in and of itself restricted the amount of viable options they had for life prolonging chemotherapy.

The data were in terms of the survival endpoint. There was a 38% reduction in the risk of death in favor of receiving lutetium plus that standard of care. And there was a 60% reduction in the risk of radiographic progression or death in favor of the lutetium and about a 50% decrease in the risk of an SSE in favor of receiving the lutetium. And in terms of toxicity, there were about 40% of patients who had low grade xerostomia, around 40% of patients who had some nausea, some of whom had vomiting as well. About 1.5% of that was high grade ground. Around 13% rate of high-grade anemia and about an 8% risk of high-grade thrombocytopenia. That was a side effect profile, generally of the drug. No new signal there. It was pretty much what we've found in previous randomized studies like TheraP and previous single arm phase two studies of the drug as well. So those were the data and we hope, as you said, that that will generate an approval around it since it's a new drug class for a patient population that really has very few viable treatment options otherwise.

Alicia Morgans:Yes, and I thank you for really elaborating on the combination and the control arm, because there has been some conversation around that. And I think it's really important to recognize, as you said, the safety data, because the study absolutely combined the agent that was going to be used in the control arm with lutetium in the treatment arm and so that safety had to be there. And also that many of these patients, even if they had not had cabazitaxel or radium actually may have not been fit necessarily by the patient's perspective, by the clinician's perspective, to pursue some of those other treatments. At least those are the patients that I was putting on study in my clinic because they just did not have real access because of whatever reason, including patient fitness. What is your perspective on the control arm?

Michael Morris: I think that the control arm has generated a lot of discussions, and I can understand that discussion, especially in earlier patient populations as to what's the best control arm for early CRPC, where there may be other viable options, but this is a very late patient population. And around 40% of these patients had both ARPIs and 40% of the population, both taxanes. Or at least for the ARPIs has had more than one. They could have had two or three. But when you look at that patient population and their treatment options, they aren't very copious in terms of things that have been demonstrated to prolong survival. So this is a treatment population where more chemotherapy is really not necessarily going to happen. As part of the eligibility, the clinician needed to feel that chemotherapy would be inappropriate for this patient in order to go on, whether that was by fitness or co-morbidities, or just appropriateness of their disease.

So as a declaration upfront, in order to register the patient, they needed to be unsuitable for chemotherapy. I think also the appropriateness of not having chemotherapy is demonstrated by the clinicians voting with their feet after the patient progressed on study. That is how many of those patients actually got chemotherapy once they came off study after progressing. And it was the minority of patients who actually did. It's not like these people were screaming out for chemotherapy during the course of the trial and then once they're off study, they can get chemotherapy. And the same was true for the radium as well. So in terms of the patient populations, quote like denial of an opportunity to get chemotherapy, anyone who put someone on this study, who should have been getting chemotherapy, did a disservice to their patient and to this study and that's just inappropriate clinical behavior.

The second thing is though, is that if they did go on study and the clinician was thinking, "Okay, well, I really wanted to give this patient chemotherapy, but they were randomized to the control arm. And so now I can't give them chemotherapy, even though they're not getting Lutetium." The median time to progression on that arm was three and a half months. So, their chemotherapy would have been deferred by just over 12 weeks basically. And if that were really the great travesty of the control arm, I would say first of all, that patient shouldn't have been on the study in the first place, but second of all, their access to chemotherapy, if they really wanted to go on chemotherapy, they would have been put on chemotherapy after those few months. And they weren't in general.

And is the difference between really viability for those few patients who did get chemotherapy, the minority of patients, that chemotherapy would have been delayed on average at a median of three and a half months. So I think there are many reasons to think that this control arm was appropriate if the clinicians were thinking about who should be on the trial, the role of chemotherapy in their regimens at that point, and the access to chemotherapy as an alternative to going on this trial, if they felt that the patients should be on study, i.e. shouldn't have gone onto chemotherapy and then subsequently changed their mind. Chemotherapy would have been delayed by a median of three and a half months. And in the end, the minority of patients went on to chemotherapy. So there's a lot of reasons to think that in this circumstance, the control arm was appropriate.

Alicia Morgans: I would have to agree with you. It was interesting, at least in my clinical practice. There were patients who ended up having that appropriate control being pain medication, or being a steroid. So these patients, from my clinic at least, could not have gotten more disease directed therapies, at least the ones that were not allowed in combination with the lutetium. And I would also emphasize that the study team re-educated investigators after an initial concern about some early dropouts on the control arm. Do you have any comments on that?

Michael Morris: Yes, as you point out there was in the first couple of hundred patients were put on this study, there was a high dropout rate on the control arm. Some have misinterpreted that as a declaration that the control arm was insufficient because it didn't contain chemotherapy. That is not the case. The control arm did contain the lutetium-177 and that I think was an issue, but in particular, one of the main reasons why the high dropout rate was seen and most of those dropouts were seen at a very few select number of centers and was not seen across the study. And at those centers, there was poor collaboration between nuclear medicine and medical oncology.

And so those patients were assigned to the control arm where they really didn't have the adequate support from their medical team to manage, which was basically a medical oncology patient, just getting the usual standard of care supportive treatments for that population. So the education efforts around that were tightening up the collaboration between nuclear medicine, medical oncology, and making sure that everybody understood the intent of the study, the randomization, the fact that the standard of care needed to be assigned before randomization and making sure that the patients, as well as the clinicians, understood the full intent and design of the study. So we should be clear that as to really what the reasons were in terms of why that dropout rate occurred and it wasn't by a dearth of chemotherapy being offered.

Alicia Morgans:I'm sure that that is the truth and really to speak to that collaboration as we wrap up the collaboration between nuclear medicine or radiation oncology if the treatment is delivered through that group. And medical oncology or potentially urology is going to be really critical as we hope to roll this therapy out, if approved. And I'd love to hear your thoughts on how we as a field can try to ensure that that happens seamlessly and is really delivered in an equitable way across our patient population.

Michael Morris: Yeah, it's an important lesson delivered by VISION because we've long said that multidisciplinary care is important. And that statement was by many just delivered or received, I would say, as "Yes, you're right but without much actual structural change in terms of how patients are cared for." But VISION showed that in those first few hundred patients that the multidisciplinary component is absolutely essential for the appropriate delivery of this therapy and the appropriate care of the patient. You really have to have the stakeholders in this treatment and in the care of patients with metastatic CRPC, especially at this late phase of the disease, which we anticipate will be the target population when it's approved.

In order to take care of the totality of the patient, the patient will have the needs for systemic treatments, either anti-cancer treatments or supportive treatments for pain, failure to thrive, constipation, dehydration, all of the things that characterize the patient who has really advanced disease, and that probably is best delivered by a host of specialists that each bring their expertise to the table in caring for that patient. And that does mean that teams of doctors need to set up formal meetings to talk to each other and review the cases, week-to-week, make sure that every all of the patients have all of their needs attended to, whether those are delivery of radiopharmaceutical needs, assessments of their overall global needs, and make sure that everybody's on the same page in terms of delivering the treatments that the patients will require.

Alicia Morgans: Absolutely. And hopefully this will bring us as a field into a better place for the care of all of our patients, not just these very advanced patients with MCRPC receiving lutetium. So, as we do wrap up now, what would your final message be to the audience?

Michael Morris: That message of multidisciplinary care is usually received as a challenge, but we should really see it as an opportunity. And especially now that we have a singularly flexible ways now of delivering care where telehealth and telemedicine are part of that model, where we don't necessarily have to have a patient in front of us in our office in order to care for the patient. We're all getting used to this, so in this period of great plasticity of healthcare delivery, we should take that opportunity to think creatively of how it's better take care of the patients who are going to get lutetium and other radio-like therapies in order to come up with the most creative ways that we can be much more efficient now, in terms of delivering multi-disciplinary care.

We used to think that it would be impossible because how would the patient physically be in two places at once and how it would practically be that the patient would go from clinic to clinic or clinicians go from office to office or building to building, and that's not necessary anymore. So we can change the way that we practice to deliver better care to our patients. If we start thinking about how we can seize this singular moment in history, where we have a new drug that we hope is going to get approved. And we're in a period where we're all thinking creatively at how to deliver care more efficiently to become better doctors to these patients and better providers by harnessing technology, new healthcare delivery systems, and helping the patients get a new therapy.

Alicia Morgans: What a message of hope. Not only will we hopefully have a therapeutic, but we may just be able to redesign our clinical structure to provide better care across the spectrum. And really collaborate more richly with our colleagues and, and have a more enjoyable time caring for these men. Thank you so much for talking through VISION with us. And of course, for the work that you do and for all the patients who have been participating under your care. We appreciate your time and your expertise.

Michael Morris: Thank you, Alicia. It's been a real pleasure and I really appreciate the opportunity to deliver the message.