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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'm so excited to have here with me today, a good friend and colleague, Dr. David Penson, who is Professor and Chair of Urology at Vanderbilt University. Thank you so much for being here with me.

David Penson: Thanks, Alicia. It's good to be here.

Alicia Morgans: Wonderful. Well, I wanted to talk with you about the rapidly changing landscape in prostate cancer, and particularly how imaging advances and some therapeutic advances, particularly in the nonmetastatic CRPC setting have really disrupted our landscape to the point that it can be hard to think about how we use our existing data for treating patients who have localized or more advanced disease, and how we really interpret those studies, and also how we design new clinical trials.

Can you set the stage for us a little bit? Tell us how new imaging, PET imaging, for example, has really impacted things like potential study inclusion criteria for patients who want to get into a clinical trial, or the way that you even practice in-clinic when you are seeing a new patient with what looks like high-risk localized disease.

David Penson: Yeah. Let's start by acknowledging that we are really talking about PSMA scanning with whatever isotope it is linked to. But the fact of the matter is, it really has been groundbreaking. This iteration of PSMA scanning seems to work. It seems to work well.

And so what we are doing is patients who previously, whether it was in the de novo setting of what we thought was localized disease or the biochemical recurrent setting, or even in the setting of M0 disease who are progressing on PSA, where previously we would never have picked up anything on x-ray ... We would say, okay, their PSA is going up, oh, they are high-risk, but they're localized.

We are now doing these studies, and we are finding lymph nodes in other places and spots that light up, and we are realizing, wow, this patient really was metastatic all along. We may have suspected it, but we are now documenting it. So that changes the game exponentially because patients who previously ...let's start in the localized space, we would have said, okay, well, yeah, they have a very high PSA, they are high grade, but I can't find any disease. So I'm going to radiate, I'm going to operate on them, I'm going to treat them like they are localized. And any trial they are eligible in, they are going to be in a localized trial.

Now, that same patient comes in, has a PSMA scan beforehand, and it shows something. Now they are M1, they are a completely different animal. They are no longer eligible for that trial that they might have been before. And we are saying, well, maybe I shouldn't be treating this person locally. Maybe I should just put them on systemic therapy and call it a day.

And we don't know the right answer, because all the trials that looked at that didn't have the benefit of this advanced imaging. So everything has shifted, even more so in biochemical recurrence. I mean, that is where I think this imaging is going to be completely game-changing.

Alicia Morgans: Well, before we get to biochemical recurrence, let's talk a little bit about these, maybe, unfavorable intermediate, high-risk, very high-risk patients, who you image, and now you have this evidence of metastatic disease. Data aside, what are you doing in clinical practice for these patients that you might have taken to the OR in the past?

David Penson: Well, I will tell you that it is very hard, at least in the United States, to get PSMA imaging on those patients because the payers do not want to pay for it. And I'm not sure that's wrong, by the way, because we do not know what to do with the information, because of exactly what you said.

Now, if someone comes in and has a positive PSMA scan and they have high-risk disease, I'm talking to them and saying, listen, it looks like you probably have metastatic disease, and based on older evidence, prior to PSMA scanning, if you came in with a positive bone scan, I would just say, we're not going to do local treatment for you, we are going to give you systemic therapy.

Now they come in with a PSMA scan and I'll say, well listen, we could do that. But frankly, earlier I would not have known this and I would have just treated you locally. Maybe we should go down that road. And as you alluded to, there is some data that says, that even in the setting of oligometastatic disease, localized treatment may have some benefit.

But it really is a discussion between the patient and the clinician, because we do not know the right thing to do in this setting. But it's not a problem I've seen a lot so far, because it's very hard for patients to get a PSMA scan prior to local therapy.

Alicia Morgans: So it's interesting, and I'm sure that varies by geography because I've been getting them more and more on the patients that I see with localized disease. And what's really interesting to me is that it is shifting what we do.  But what we are trying to not do is withdraw our intent for that local therapy like you said, because we do include those patients on the prior clinical trials that we have, where we do have the evidence. And to remove that possibility that we might be able to cure these patients just seems a little premature.

At the same time, we don't traditionally think that we can cure patients with metastatic disease. So it's a multimodality approach, usually, in our clinics.

David Penson: But it was going to be anyway, right?

Alicia Morgans: Yes. Yeah.

David Penson: I think it's just a matter of discussing with the patient. Saying, look, before I had this test, I would have just treated you locally, seen what happened afterward, and decided based on your response to treatment and/or put you on a clinical trial.

Now I have some additional information, but I don't know what to do with that information. So as long as we are both aware that I do not know the best thing to do and we can walk through it together ... I think, and I'm treating patients the same way. They come in with a positive PSMA scan and I look at them, I go, listen, two years ago I would have just said, let's go to the operating room. I'm a surgeon, as you know, and hope for the best.

Now I'm saying to them, look, I may not be able to "cure" you with local therapy, but I can start you down the road to prolonged remission, and hopefully an effective cure.

Alicia Morgans: Yeah. It is really, really interesting. And the other place that you mentioned, which is really interesting to think about the application of this, is in the biochemical recurrent space. So what do you think there? And let's talk hormone-sensitive, biochemical recurrence.

David Penson: That, to me, is where everything changes because previously we would see these patients who would come in and who had been treated, whether it's with surgery or radiation, and now they have a detectable PSA or a rising PSA. Maybe they have a very rapidly rising PSA, and you would get a bone scan and a CT scan, and it would be negative. You were basically treating a blood test with medications that do affect the quality of life.

You didn't know if you were doing the right thing. You felt like you were, but you didn't know it for sure. PSMA scans now say, okay, I found the disease, alright, I know it's there. So you feel better about initiating treatment. But let's be very blunt, who knows if that really makes a difference, treating them as soon as you see them on a PSMA scan, or say, a year later when they have radiologic evidence of disease on conventional imaging.

We do not know that. But it is fascinating because all of our studies are based on conventional imaging. So what do we do with the information we have with regard to hormone therapy, novel agents, other systemic treatments when we don't know when to use them in the setting of PSMA scans? It's a great time to be in prostate cancer care because we are getting new imaging, getting new treatments and we are reinventing the wheel in a really positive way.

Alicia Morgans: Yeah. I would agree with that. And I would also say, I think it is so interesting to be involved with patients because, as you said, these shared decisions are coming up over and over again. And also so exciting to be able to collaborate across our disciplines, having our radiation doctors sometimes come into the biochemical space, give a little SBRT, maybe we give some hormonal therapy too. Maybe we don't.

It is truly a Wild West in terms of what we are doing, but we're doing it with our patients and our colleagues in real-time, which makes it really, really interesting. Hopefully, we will get some data soon that will help to inform our decision-making, but it's really fascinating in that way.

David Penson: Oh, and the other thing, and you and I were talking about this before we started, it does change the trial design. When you say we're going to get data soon, I don't know how soon we will get that data because what we've done is we've created a bit of lead time with PSMA scanning.

So instead of getting an outcome, primary outcome, in three to five years, it may be five to seven years or even seven to 10 years. And so we are waiting again, which will drive all of us crazy, will drive our patients crazy, but we probably have to do it.

Alicia Morgans: So to that point, where does metastasis-free survival fit in? If you're thinking about trial design, we've based many of these trials on metastasis-free survival by conventional imaging. We do know that is tied to survival in this population that we are discussing, and PSA has not really been a reliable endpoint. Where do we go if we keep adjusting where MFS is actually going to fall out because we're intervening before patients get to MFS? Appropriately, there are approved agents, therefore nonmetastatic CRPC, but where do we go?

David Penson: Well, in the end, the fact that we got to MFS was, frankly, an incredible thing. There is no other way to put it. To have the Food and Drug Administration, which is an inherently conservative, and rightfully so, institution, accept MFS as an acceptable proxy for overall survival, was one of the most eyeopening things I've seen in my career.

And credit to the IceCap group and the people who did the work. I don't see them throwing away MFS, and I, frankly, think that PSMA imaging will be a reliable proxy of ... a reliable way to measure metastatic-free survival. But the problem is, the time from the proxy endpoint MFS to overall survival is going to stretch out, so we are going to have longer trials.

I don't see us ever getting to a point where PSA becomes a reliable proxy in any ... whether it's localized disease or even advanced disease. It's just not a reliable enough endpoint. So I think we are going to have to accept the fact that this is what we are stuck with.

But on the other hand, look at it this way, it's bad in this ... PSMA scanning is going to be bad in the advanced disease setting as far as trial design goes because it's going to stretch things out. But in the localized setting, it's going to shorten the window, so we will get more answers in localized diseases quicker with PSMA scanning. So, it's both a blessing and a curse.

Alicia Morgans: Absolutely. And as long as it leads us to the right answers for our patients, I think we are all going in the right direction. It's just really an interesting time to practice prostate cancer.

If you had to summarize all of this mess, with the rapid evolution of PSMA PET imaging, new approvals for nonmetastatic CRPC, use of MFS, what would your summary be?

David Penson: I'd tell you what I tell patients because I think ... maybe I'm just an eternal optimist, or a delusional optimist, as someone once referred to me. We have so many new options in imaging and treatment. I look at it and I say, there are a lot of questions that we need to answer, but the fact that we have a lot of questions is great news for patients. And in the end, this is going to change the way we practice.

It may take a little while to figure out the best way to do it. But the fact of the matter is, I think advanced imaging is here to stay. I think it is going to be treated like conventional imaging in the long run, just because we can't wait five to 10 years for the clinical trials. And as new treatments come along, I think that it is going to be very positive.

Alicia Morgans: I could not agree more. I will be an optimist, we will call ourselves, with you. And I think it is all in the best interest of the patient. So thank you so much for your time, your insights, and your expertise.

David Penson: Thank you, Alicia.