Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Michael Morris, who is the Prostate Cancer Section Head at Memorial Sloan Kettering and a Professor of Medicine. Thank you so much for talking with me today.

Michael Morris: Thank you for having me, Alicia.

Alicia Morgans: Of course. So I wanted to talk with you a little bit about one of your areas, many areas, of expertise, which is on advanced molecular imaging and how we as a field take the data that we have, which unfortunately is more gray than black and white, I think at times, and integrate that into our clinical practices now that more and more of us are having access, to some degree or another, to molecular imaging. So, what are your thoughts, and where do we go from here?

Michael Morris: So much of our clinical practice is dependent on what we have access to in terms of imaging modality. Most of us in the US, in terms of molecular imaging, it's going to be Axumin® scanning or fluciclovine. For the rest of the world, probably PSMA, or prostate-specific membrane antigen, is the basis of molecular imaging, so there is a disparity right there. But I think that regardless of which imaging modality you're talking about, there are both opportunities with these modalities and there are drawbacks, as is true with any new technology. What are the advantages? Well, probably all of these detect disease with greater accuracy than what we have right now, which is CT and bone scan as the most common way of imaging prostate cancer.

What are the downsides? Well, with that additional lesion detection and reclassifying patients now according to molecular imaging as opposed to what's apparent by standard imaging, there's a lot more confusion as to what to do with that information. And I think if you're a practicing doctor, whether you're a urologist or radiation oncologist or a medical oncologist, what to do with that information is really a struggle because we have very little data on what the actionability of those and how to contend with those new lesions and new areas of disease that we can now see that we couldn't see before.

Alicia Morgans: Absolutely. It causes such stage migration. And then we have other tools and toys that we play with. And so we might see some new metastases. And then we start zapping oligometastases. And then it leads to enhanced systemic therapies. And so it actually can be, it can really compound some of the other challenges that we have.

Michael Morris: I see it in many ways as the new PSA. When we introduced the PSA into clinical practice in the 1980s, there was a lot more detection of prostate cancer and much earlier detection of relapse because you didn't have the lag between, that is now defined by biochemical relapse, between your primary therapy and your metastatic disease. And we had this new indicator of treatment failure that we all acted on, so we were doing a whole lot of maneuvers, whether those were excessive prostatectomies or too early termination of treatment or too early initiation of ADT when we had a rising PSA after a surgery or radiation. We face those same risks now. We are going to detect disease relapse earlier. We're going to react to treatment-related changes that we're going to see a lot earlier than we used to. And the hazard is we're going to do things that impact patients, their treatment, the duration of treatment, their classification in ways that we don't fully understand now because those trials haven't been done.

Alicia Morgans: I love that analogy. I think that's fantastic. And it took really the Prostate Cancer Working Group to define, "these are disease states, this is progression, think about holding to clinical progression or radiographic progression."

Michael Morris: Yeah.

Alicia Morgans: And I really look forward, I'm sure you're still involved with the Prostate Cancer Working Group, and I look forward to seeing that group put together some guidance for us as we're waiting for some of the data to come in. But that's a wonderful analogy.

Michael Morris: One of the good things that Working Group did is that it said ... Well, we demonstrated over the course of several clinical trials and over 8,000 patients, don't react to PSA. React to usually bone scan changes as an indicator of treatment failure. So now we are in many ways resetting the clock because we now have PSMA based imaging that is ubiquitously available across the world, except for the US, but still, it's going to indicate that a patient may be beginning to progress through treatment much earlier than a standard bone scan would have. And so we have to repeat all those validation studies to define what's a clinically meaningful indicator of when it's time to stop treatment, of when a treatment is no longer working.

Alicia Morgans: Because we certainly don't want to give up on something if there's still mileage in it.

Michael Morris: Yeah. Now what we have is a PSMA scan that's performed mid-treatment. You see the emergence of one new lesion. The next thing you know, the patient is in front of a radiation machine getting that irradiated, something that we have no idea as to whether that is clinically useful or not, but is expensive to both the patient and society.

Alicia Morgans: Absolutely.

Michael Morris: There's all of these reactive maneuvers that we're making without knowing whether they're meaning meaningful or not, just like we were doing 10 years ago with the PSA.

Alicia Morgans: Really interesting. So one of the other things that we touched on today, and Piet Ost was there as well. And actually I thought he gave such a balanced overview. It was very much appreciated. But this oligometastatic delay time to potentially delay time to initiation of ADT, but is that really meaningful? Can you comment on that a little bit? What are we really doing when we're dealing with metastatic therapies?

Michael Morris: That oligometastatic dilemma occurs in a series of contexts. And the context that he was talking about was when a patient is not on ADT. So, let's say after their primary therapy is done, and they progress in a limited number of sites. And so, as an alternative to initiating ADT, you instead irradiate those oligometastatic sites.

Alicia Morgans: And they're only detectable by molecular imaging. That was the other piece, I think.

Michael Morris: Yeah. He conducted a clinical trial in which hormonal therapy was held so that oligometastatic directed therapy could be delivered via radiation. So, of course, we don't know whether that's the right maneuver or not. We now have hormonal therapies in the contemporary era that we know in all sorts of contexts prolong survival when applied. We just don't know whether deferring those in deference to radiation to these oligometastatic sites is better, indifferent or worse than doing either oligometastatic therapy in combination with ADT in a new agent, which I would say may indeed amplify the effects of the radiation, or whether it should be given in lieu of it, or whether ADT and a novel hormonal therapy should be given in lieu of the radiation therapy. We just don't know.

Alicia Morgans: But there is a trial that's coming out that may help guide us, right? Well, it's not coming out yet. It's just actually launching. The STAMPEDE trial is actually doing an oligometastatic arm.

Michael Morris: Right, but the STAMPEDE trial is looking at a newly diagnosed metastatic disease, but where the metastases are oligometastatic, so patients who have five or fewer metastases will be eligible. With untreated primaries, they'll receive one of a number of different possible standards of care for systemic therapy and definitive treatment of their primary with either surgery or radiation, and that would potentially involve the pelvis as well, and radiation therapy with stereotactic radiation to those metastatic sites. So that's a little bit different from the patient that we were talking about in Dr. Ost's session in which that was definitively treated patients who have now relapsed systemically at a limited number of sites. But both of these really bring up the need for further data. They're different contexts. There are trials addressing oligoprogressive disease as well. It's great to see that we're actually answering these questions now, and we'll have the answers in a few years.

Alicia Morgans: But just to get back to imaging because that's really what I did want to talk to you about, and you have such an expertise there. If you could tell the listeners one thing about ... Where one patient ... Is there a patient where you think advanced molecular imaging is most useful? And maybe it's more than one patient, but let us know, who is that person?

Michael Morris: So I think that there are some scenarios where we could say molecular imaging does make a difference in terms of understanding what our patients should or shouldn't get. So if you took, for example, a patient who has high or higher-risk localized prostate cancer, and is about to go to surgery, and the plan is surgery alone. And you do a molecular image, and you find that there is a positive lymph node that lies just outside the operative field, or if you find that that patient has actually distant disease that otherwise the patient would not and you would not have known. I'm not saying that surgery should be abandoned by any means. We just don't know that ... Or that the primary shouldn't be addressed. But you've identified a patient with systemic disease, potentially, who would otherwise not be receiving systemic therapy. That's when I think that you could entertain a multi-modality therapy which would address all of the patient's components of his disease, where otherwise you would have just been addressing one.

And then, doing nothing, that patient would be destined to relapse because he hasn't had most of his disease addressed, and you are at least understanding of the patient's problems better. You don't understand quite how you should react to it, how to deal with that otherwise undetected systemic disease, but you do know that your old treatment paradigms would not achieve the aim, which would be cure, had you just done standard imaging.

Alicia Morgans: Absolutely.

Michael Morris: So, now there's no circumstance where the imaging provides the definitive answer, but it does allow us an insight into why our patients relapse when otherwise we would not have known, and should push us to put those patients on clinical trials where otherwise they might not have gone.

Alicia Morgans: Absolutely. And there is a trial that's allowing that or at least ... There's several probably. But can you tell us a little bit about, there's a trial that I think is being led by your colleague, Mary-Ellen Taplin.

Michael Morris: So yeah, there are actually a few such studies. One of them is called the Medicure study, which actually has a number of different arms on them. But two of those arms allow for patients who have molecularly detected metastatic disease to receive multi-modality therapy that the protocol outlines depending on the context. Those treatments involve either ADT plus one novel hormonal therapy or ADT plus two novel hormonal therapies, depending on the randomization, plus radiation therapy to the oligometastatic sites, plus definitive treatment of the primary. That's one of those arms. Another one of those arms is for relapsed patients after their definitive therapy, and allows for treatment of oligometastatic disease. So, there are trials that are exploring in the Phase II context and, for STAMPEDE, in the Phase III context sort of how to best address these clinical dilemmas that we all face.

I don't want to come off like I'm seeming negative about these. These are very useful tools. They're allowing us insight into the patient's disease that we never would have had before. But with new knowledge comes new responsibility to figure out what to do with that knowledge. The wisdom isn't in the scan result. The wisdom is how to use that scan result to the best effect on the patient.

Alicia Morgans: Absolutely. And that I think is what we're still trying to define.

Michael Morris: Yeah.

Alicia Morgans: So, as we move into this next era, do you have any sort of parting thoughts or words of wisdom that you want to give to clinicians? Because they're gaining access to these scans, and they don't always know how to best use them.

Michael Morris: Right. I think that the first word of wisdom is to ourselves, and not necessarily to the patient ... in terms of how to treat patients. We have a new tool now. And it's incumbent on us as a community, that includes radiation, surgery, medical oncology, and most importantly radiology, which historically hasn't been involved in the merger of therapeutic studies and radiologic studies, at least in prostate cancer. As a community, we owe it to ourselves and to our patients to do these trials incorporating novel technologies. At first, that will be a challenge, to figure out how to incorporate it because once you have information, you sort of can't ignore it. So that is a design challenge of how to incorporate molecular imaging, still study molecular imaging, and not have it be randomized to either pay attention to it or not pay attention to it.

So it's not like your typical biomarker study where you're just collecting the biomarkers and you'll analyze it later. Here, everybody sees what the result is, and it would be very hard and ethically challenging to know that a patient has a distant disease or something and not pay attention to it. But the other thing is, we owe it to our patients to acknowledge that we don't always know what to do with this information, explain that to the patients that we may be getting something that actually brings us into territory where there is no expert on what the right way to react to it is because we just don't have that knowledge. And then approach our treatment changes that we make in relationship to those imaging findings very, very carefully because we may be heading into an area where we're actually doing harm, or at least not doing good and putting a patient's if not their health and their wallet at risk by reacting to it in an inappropriate way just because it feels good to see something and treat it.

Alicia Morgans: Absolutely. Well, I love the analogy of thinking of this just as we did when PSA was coming to light, that there's a risk for many more patients to be detected, then that risk for over-treatment, and a lot to learn.

Michael Morris: A lot to learn.

Alicia Morgans: A lot to learn.

Michael Morris: Yeah. It's a good kind of problem to have a really new, useful tool which really transforms the prostate cancer landscape, but we not only have to redefine all of our treatments, but all of our risk models because now we have something that actually declares that a risk ... what we always thought would be a future event and a risk model that predicts that event. Well, now we can detect that event much, much earlier, so all of the models will need to change as well.

Alicia Morgans: So, a lot of work for both of us to do, it sounds like.

Michael Morris: It's a work born of success though.

Alicia Morgans: It is. And at the end of the day, it's going to help our patients, if we do it right.

Michael Morris: If we do it right, that's the key thing. We have to do it right.

Alicia Morgans: Absolutely. Well, thank you so much for your time and expertise today.

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