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

Michael Morris: Thank you, Alicia. It's a pleasure to be here.

Alicia Morgans: Well, always a pleasure to talk to you. And today, I'd like to talk to you about something that I think, is a little disruptive because we are being disrupted, thinking about lutetium coming into our clinical sphere and how we can really come up with ways to implement lutetium in our clinical practices in a way that ensures equity to all patients, regardless of the many factors that could really disrupt that. So, what do you think about the implementation of lutetium, we'll take it step by step because it is a big question.

Michael Morris: Sure is. And it's a really important aspect to a pretty exciting introduction of a new therapy and to the family of therapies for prostate cancer with a really great potential to help people. And we need to make sure that, that help, this modality is available globally. This is not an issue restricted to the United States, but globally on an equal basis or an equitable basis. I think the first thing is of course if the therapy does require, which I think it probably will, a PSMA PET scan in order to select for the appropriateness of treatment, the first issue of equal access is really the availability of PSMA PET and for this purpose. And as we know, a PSMA PET is not available, even for its currently labeled indications, on a uniform basis throughout the United States. It is highly dependent on geography and dependent on the insurer and reimburser. So, that is the first factor.

The second is having a nuclear medicine, or really a multidisciplinary team available to administer the treatment and also to care for the patients. So, it's going to require a real build-out of nuclear medicine capabilities in some communities and those communities may not have the resources to do so because of the general socio-economic condition of those communities and the general health of their population and what those needs are. So, there's that physical plant that needs to be built out and the expertise from a multidisciplinary group that many communities may not have.

And then the last issue is how many tests need to be packaged with the patient to deliver the best treatment to that patient. So, per the VISION trial, all that is really needed is a PSMA PET, but there is much discussion both at this meeting and elsewhere about whether other assessments should be performed in conjunction with the PSMA PET to best select those patients and proposed have been a number of other tests such as FDG PET, CT-DNA and assessing the patients HRD status or P53 status. All of those have been brought up in yesterday's sessions on PSMA directed therapies. And I think all of those raise questions of what the social resources and the healthcare resources available are, who is going to get what tests, and how much personalized medicine is appropriate for the general population versus those privileged few who can afford all of those tests and how much value is actually derived from those tests in terms of identifying patients who will benefit. It's a whole host of issues.

Alicia Morgans: It's a whole host of issues. Let's talk first about the imaging component because, in the VISION trial, the large majority of patients who were eligible by the criteria had a positive PSMA PET scan, quite a large majority and this is a heavily pretreated population. And this population doesn't necessarily have a long lead time before their disease can start to cause problems. One of the issues with PSMA PETs, even as you said, we have an indication, we've got approval. We have centers that are doing these, although it's not equally distributed. Even in those centers where we have PSMA PET, there can be wait times of four weeks, six weeks plus, because we do not always have enough ability to scan the number of patients who need to be scanned, and this is not including patients with metastatic castration-resistant prostate cancer. So, if we also then have to do these and we also then have to do FDG PET or other tests, what are your thoughts on the timelines alone and how that might affect patients?

Michael Morris: I think that timelines are of concern and absolutely, we have experienced that even at a big center like ours where you do not want to be delaying a necessary treatment because either you have tracer availability issues, and in the age of the pandemic, also the staffing to do all of this additional imaging. Camera availability in some centers is an issue. So, there are a lot of practical concerns.  But the other issue that you just raised is, it is not just a PSMA PET, but these other assessments as well. And there are really two schools of thought on this, both of which have really legitimate claims. And the first is that you should do as many assessments as you can to give you the confidence that you are best assessing a patient for a given therapy because there are other therapeutic choices in some patients, especially in this patient population that VISION represented. Some of those patients may not have yet received cabazitaxel.

And you're trying to distinguish who should get cabazitaxel versus who should get lutetium. Those who are supporting the use of FDG would point toward the TheraP trial in which the dual imaging positioned allowed for the identification of patients who had PSMA positive, or PSMA negative but FDG positive disease or heterogeneous PSMA expression. And those patients perhaps would not have done as well. On the other hand, Mike Hofman presented data at yesterday's meeting in which the PSMA scan was shown to be a predictive biomarker and that would strongly suggest that patients should be getting a PSMA PET because those with strong expression of PSMA do the best with the therapy. He presented data on FDG as a prognostic indicator and prognostic indicators just indicate with or without treatment who will do well and who won't. Now that does not actually at face value support the role of FDG PET in making a decision.

And indeed, there has not been any prospective data that would show that the patients in VISION, who only got a PSMA PET versus those in TheraP who got both, what that outcome would be, whether the FDG is actually useful. Many have pointed to a 20% improvement in terms of PSA response in TheraP versus VISION. But PSA is not predictive of overall survival, generally speaking. And it does add social costs to a test.  Otherwise, if with the lutetium, if you must get a PSMA scan, if you must get FDG, if you must get CT-DNA, you are talking about a therapy that is going to be expanding on the social inequities in the healthcare system. Those costs must be drawn from someplace. It isn't anti-personalized medicine if you say that those social costs need to be considered.

And I also think that from a justice standpoint, there has to be good data to support that. And where is the prospective data with the survival endpoint to indicate that FDG actually does contribute to identifying who will respond or who will not respond? A prognostic indicator doesn't do that. There are many prognostic indicators that we have in prostate cancer such as distribution of disease, the volume of disease, presence of liver metastases or not, Gleason score, et cetera. There are many but we do not use those unless they are proven to be predictive to make treatment decisions or not. So, I think that those issues really need to be thoroughly discussed, not just on an individual patient level, because you are always responsible as a clinician for the individual patient in front of you. But somebody does need, and I think that we need to be part of that conversation on a social level. What's good for society and per VISION, the only thing that was used and demonstrated to be part of the eligibility process of identifying who would be on that trial or not was a PSMA PET.

Alicia Morgans: I agree and I think my concern is also that if you apply the data from VISION but then you say, "Well, we should just select more effectively with FDG." There are clear equity issues that are going to be raised. You will be denying patients who would be eligible by VISION of a treatment that prolongs life and that does not seem like the best answer. Plus you are adding in extra cost and time and hurdles essentially for patients to get a life-prolonging therapy. I have issues with that and concerns about that and I think we all do. If we frame it differently, we can say we're being more precise but we are also being more restrictive. And is that the right thing to do when we have a phase III trial that shows survival benefit?

Michael Morris: And precision medicine is dependent on data and not on [inaudible]. My concern is that there are a lot of very dogmatic statements that are being made without the supporting data. And that does generate what can for generations be passed down knowledge as truth, rather than a much more open-minded discussion of, "This is what we believe but this is what we know." And what we don't know is prospective with a hard clinical endpoint, whether FDG actually does predict for a response and clinical benefit. And I'm happy to entertain the possibility that it does but on the other hand, folks who are very dogmatic about this need to entertain the possibility that it doesn't. And so, there needs to be some discussion then about what you do about that gap between what you suspect and what you know.

Alicia Morgans: That's true. A prognostic biomarker is not sufficient to withhold that treatment, from my perspective, although it is very intriguing and I think deserves a prospective assessment. And in TheraP, we excluded the patients who could have answered that question, and that is a concern.

So, we have discussed imaging and clearly, it has effects on our implementation of lutetium when that is approved, if approved. What else are you thinking about in terms of this process? I know you mentioned the multidisciplinary collaboration, which can also be limiting, particularly as you mentioned in certain geographies. Do you have suggestions on how teams can work together and leverage perhaps others, even if they are at a distance and not in the same institution? Are there suggestions on how we can get this treatment to the patients who need it?

Michael Morris: Sure. There are many things that have been dismissed in the past as not feasible because of logistics and economics, like multidisciplinary clinics that in today's day and age, we've had a very disruptive force in terms of the pandemic, allowing us to rethink what we used to say, "No," to as now saying, "Yes." The greatest example, of course, is the pandemic forced everybody who is very skeptical about the feasibility and the safety of virtual medicine through telemedicine and telehealth to actually demonstrate that it actually can work. And indeed prostate cancer is one of the most amenable diseases to those virtual clinics because many of the patients are there for discussion and are actually not sick but they would like to discuss their treatment possibilities. It's a disease with a long treatment course.

So, we need to revisit this issue of whether telehealth is possible to create those multidisciplinary opportunities because now we will accept those different models. Multidisciplinary care does not have to be in proximity to the physicians or even to the patient in order to capture. That could even be commercialized, if in a system like ours that has to be part of the incentivization, but people can bring to bear their expertise on patients without actually being in each other's clinics or being in each other's cities or even being with the patient at all. So, somebody of course needs to take ownership of the patient, needs to examine the patient, and provide all of those other experts with those opportunities. But I do think that in today's day and age, if we can't reimagine how to do multidisciplinary care with all that we've learned over the last two and a half years, then perhaps we have the wrong people thinking about it.

Alicia Morgans: Well, that is quite a gauntlet to throw down but I think we can rise to that. And I love that example of how we have really survived and hopefully are starting now to thrive in whatever we live in now, post or during a pandemic.

Michael Morris: I think even in the post-pandemic period, those models are here to stay because patients really do like them. And it works for many clinicians as well. As long as the reimbursement policies continue to support that, I think what gets in the way right now in terms of enacting those multidisciplinary models is licensure. And when policy interferes with good care, that's when policy needs to be changed. And people like us who are responsible for patients need to speak up on those issues.

Alicia Morgans: Well, thank you for raising all of these concerns and also for just helping us as a community think about how we are going to implement this transformative therapy when we have the opportunity and not just to help patients on a one by one basis but to consider speaking up and continuing what we know is going to work for our patients. Whether that's telehealth, ensuring access, and ensuring equity of distribution of this therapy to all those patients who need it. So, thank you.

Michael Morris: Thank you, Alicia.

Alicia Morgans: Thank you for your time and expertise.

Michael Morris: It's my pleasure.