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Neal Shore: Hi, everybody. I'm Neal Shore. I'm the medical director of Carolina Urologic Research Center. What a great pleasure for me to be on this program, this call today with my dear friend Judd Moul. Judd is a professor of urology. He has an incredibly illustrious career at Duke and before that at Walter Reed Medical Center. He's a professor of urology. He has done a tremendous amount of clinical and basic science research, and he's a very gifted surgeon. I think on behalf of myself and Judd, and Judd was the first author. We're going to first talk about a paper called, "Biochemical recurrence in patients with prostate cancer after primary definitive therapy, next generation imaging, and treatment based on risk stratification."

This was published in Prostate Cancer and Prostatic Disease. And so this is a commentary is funded by Pfizer and Astellas, the co-developers of enzalutamide. And we received medical writing assistance from Pfizer and Astellas for this. So thanks very much.

Judd Moul: Well, Neal, first, it's great to be here and always a pleasure to work with you. We've done a lot of projects over the years. And especially, since you're a Duke alumnus, it's extra special to work with you. So thanks a lot. So we wanted to write this review paper because PET scanning is exploding in our field of prostate cancer. As we all know, up until a couple, two, three years ago, we really didn't have much other than bone scans and CT scans. And while those were really helpful over the years, they weren't very accurate to determine early metastatic disease with low PSA levels. So PET scanning, particularly the PSMA PET scan, and there are now several different slight variations on the market, have been a real game changer in managing our patients, particularly men who have a biochemical recurrence after surgery or radiation. And also to work up high risk men who are newly diagnosed.

Neal Shore: And so it's a big learning curve now compared to this conventional imaging, as you say. CT scan with and without contrast and technetium bone scan. And so now we're getting these PET PSMA scans, different tracers, gallium fluorinated tracers, more to come, probably some copper tracers and others. But how do you see that changing the actual clinical utility in the real world?

Judd Moul: So in the real world, you and I and others in our field, we've dealt with biochemical recurrence for the last 20, 25 years. I think the first review article on PSA recurrence was in about 2000, so 23 years ago. And that was based on men who had a negative bone scan and a negative CT, but a rising PSA after prior localized treatment for prostate cancer. Now, with PET scanning, we're finding this microscopic disease earlier. And for one thing, when we wrote this review paper, and I remember you and I and the other co-authors, we really weren't mindful of this issue of PSA recurrence. And I think one thing, it's going to change the definition of biochemical recurrence. True biochemical recurrence would be patients who have a negative PET scan. And then semi biochemical recurrence would be negative conventional imaging but have a positive PET scan. And we really don't know exactly what that means from a prognostic standpoint.

Neal Shore: Yeah, I think that's a really great point. We have some phase two studies. Oftentimes, people acknowledge them, they're good studies, but they're just phase two, called STOMP and ORIOLE. By and large, I think it's safe to say that if we can find early disease, either on conventional imaging, maybe now even with PSMA PET when conventional imaging is negative, are we going to try and do a focal spot radiation SBRT and see if we can delay the onset of androgen deprivation therapy requirement? Having said that, we're into this unchartered territory, aren't we? Where we don't have a lot of level one evidence of what to do if the PET PSMA takes a conventional imaging, which shows low volume disease and potentially converts it to high volume. Or no volume disease and conventional and says now you're low volume. And then there's probably some intermediate in between that. And so I think these are really exciting times. What we do know is 20 to 40, 50% of our high risk patients who have surgery or radiation will develop biochemical recurrence. So I think this is an area that's really ripe for additional trials.

Judd Moul: That's a great point. The one area that I'm concerned about is we still have a lot of uncertainty when the PSA is between 0.1 and 0.5, especially on our surgical patients. That some of these men might have some residual benign prostate remaining in situ that can cause a little PSA presence, if you will. And in my own clinical practice, I'm still quite reluctant to pull the trigger for a PSMA PET when the PSA is less than 0.5, simply because I know it's not as accurate in that range. And I'm mindful that some of my surgical patients, I may have left a little prostate growth inside the bladder neck because we do a bladder neck sparing. Or I may have left a little BPH nubbin in the urethral stump because we do a urethral sparing technique. And so I just want to make the point to the listeners of this program that be mindful when these low PSAs, and don't be too aggressive to over treat, and just be a little bit skeptical.

Neal Shore: Yeah, I think great points. A, when do you pull the trigger for the PSMA PET? Some of the research and academic studies have said that you can find about a 60% accuracy or positivity with A PSA as low as 0.2, 0.3. I'm like you, I tend to wait till around 0.5. I think part of that may be related to the PSMA PET you're using, and maybe part of that's also related to your interpreter. I think a lot of our nuclear medicine radiology colleagues are really learning from our academic leadership in both Europe, and the US, and around the world.

And then you make a great point, the doubling time. So if it's a low PSA, maybe it could be from BPH, it could be from malignancy, but I think the doubling time, and maybe that springboards us to the discussion about EMBARK, is how we think about is a patient at risk. Are they low risk or high risk with their BCR? And great work from our friend and colleague, Steve Freedland back in the day looking at the large Hopkins series really was one of the first to show that doubling time after surgery.. And again, we've seen this in radiation, the rapidity of the doubling time really does matter, especially when it's less than nine or 10 months.

Judd Moul: Congratulations are an order to you. After we wrote the review articles together in Prostate Cancer and Prostatic Diseases, then boom, the EMBARK trial was recently published in New England Journal of Medicine. And you were a senior author on that. And as you mentioned, Steve was the first author. Let me just ask you, since you are intimately involved with that study and presented at the AUA. From a practical standpoint, who should I be thinking about for either enzalutamide monotherapy or combined androgen blockade with ADT, plus enzalutamide in these biochemical recurrence patients? Because this is a brand new area for us as urologists. So I look to you for expertise.

Neal Shore: Well, I'm working through this just like everybody else, and I really appreciate your question. Since we published our Prostate Cancer, Prostate Disease paper, and since we published the New England paper just a few weeks ago, the FDA just approved or it expanded the indication now for enzalutamide for our BCR patients, for those who are high risk. So high risk BCR patients who have a rising PSA after prostatectomy, or radiation, or both. And so as you know, it was a three arm study really comparing combination enza ADT, versus ADT alone. As well as, another arm that just looked at monotherapy enza, versus monotherapy ADT. And the combination ADT-enza, monotherapy enza, both of those arms bested monotherapy ADT. And so the FDA just recently gave a label expansion. And I think it's great because to your point of your question, now we have an option to think about, "Okay, do I do combination ADT-enza or do I just do enza monotherapy alone?"

I think a lot of things go into that decision making. Of course, good discussion with the patient. Maybe it's ideal for a patient who's sexually active, their libido is important to them, and they may want to just consider the enza monotherapy. Maybe they want to consider enza monotherapy, if there's someone who's really worried about QT prolongation that we see sometimes with the T-suppression drugs. Maybe there's concern about bone demineralization, maybe there's concern about fatigue. Or maybe these are not as pressing issues and they want the best opportunity to delay metastasis free survival, which was the primary endpoint of the EMBARK trial. We didn't yet achieve OS, but it's certainly trending positively in both the combination and the enza mono arm. So I think what I love about the study is it's opening up this really thoughtful discussion that we can have. We have choices now, and I think that just monotherapy ADT is no longer a standard of care, best option.

Judd Moul: Really interesting. And thanks for that answer. I would say it brings back so many fond memories of we were using bicalutamide monotherapy about 10, 15 years ago in the same indication, even though we had much less evidence than we do now for enzalutamide. The EMBARK trial is literally the biggest and best study that's ever been done in biochemical recurrence. So we have these answers. But here's a practical question. Back in the day when I was using bicalutamide monotherapy to treat PSA recurrence, we were seeing a lot of breast gynecomastia. If I pull the trigger for enza monotherapy for a patient with biochemical recurrence, is it appropriate to do radiation oncology referral for prophylactic breast irradiation?

Neal Shore: Yeah, I think it absolutely is. And it's a great question. And we're learning a lot as we expand our therapeutic options. There's no free lunch, right? Enza monotherapy with unopposed T-suppression. So when you're not dropping T, and you're just blocking the AR, we saw in our 350 patient arm in EMBARK, we saw this in the ENACT large phase two trial. We've seen this in other monotherapy, ARPI, small phase one and two trials. You'll see more gynecomastia, you'll see more nipple tenderness and discomfort because you're having this unopposed increase in estradiol.

Now, you can prevent or prophylax, as you say. And prophylactic radiation to the breast bud tissue is highly effective and it can be done in one to three sittings. So it's quick. Other ways of addressing this is aromatase inhibitors. And even interestingly, a sub-areola removal of the breast tissue on an outpatient basis. Now, I think we're learning a lot with these different options. One's a pill option, one's radiation, one's a surgical. I think we need to continue to investigate this, and look at the costs, look at the morbidities, and really be better to advise our patients on how to think about this.

Judd Moul: In the EMBARK trial, we had a stopping point if the patients got to a low PSA. And in fact, I'm smiling because I enjoyed very much participating in the trial, although it was very difficult to know that the PSAs were blinded. So that makes the trial even more valuable that we were blinded to the PSAs. But here's my question, clinically. Clinically, how should doctors manage the stopping of the enzalutamide? And do you think that... Did the FDA put anything in their label about giving the patients enza or ADT break, as we did in the EMBARK trial?

Neal Shore: There really isn't anything in there. And that is one of the really nice aspects of the trial when we designed it. If you could nadir your PSA to less than 0.2, regardless of the three arms, we had patients get an interruption. Or I think the word I like for patients is a holiday and being off therapy. And you continue to monitor the patients closely. Monitor their PSAs. You can monitor their testosterone. Of course, monitor their symptoms.

And I think overall, patients love that ability to have a holiday. They just generally feel better, whether it's a lack of taking therapy, maybe there's some level of placebo effect. But I think that having less drug on board and knowing that you can go back and reinstitute therapy. So I think that's going to be additional learnings from this study. I think additional trials that we may want to think about prospectively, especially on further looking at other validated sexual function questionnaires that a lot of folks are working on. But I think from a value-based healthcare standpoint, having those holidays for patients is going to be very appealing, both from an economic outcome reporting sense, but also from a quality of life standpoint.

Judd Moul: So again, just from my perspective, having participated in the trial, and if I'm talking to my fellow urologist about it, for most of my patients, number one, if they're a high risk biochemical recurrence patient, I'm going to be counseling them about enza monotherapy. And I'm going to be counseling them about combined blockade, but I'm also going to generally, whatever they choose, I'm going to be getting a PSA at about six months. And if that PSA reaches below 0.2, I'm going to stop the drugs and give the patients a drug holiday. And I think it's great that we're making this point to practicing urologists. This is a whole new area for us or a whole new body of knowledge.

Neal Shore: And it really is. And I love how you're thinking about it with all your great experience. And when you bring it back to the next generation imaging, we're all going to continue to learn and how to improve upon optimizing care, which is everybody's North Star, so to speak. I think it'll be really hard to do a trial like EMBARK again. Eight plus years in the making, global perspective, over a thousand patients. But we got it over the finish line and it's changed the way we're going to offer clinical care options. And the great thing about what you and I have been doing throughout this and so many of our colleagues is this continued evolution of biomarkers, imaging, and therapeutics. So Judd, it's been a great pleasure for me to talk with you about these two papers, these two really important educational opportunities for our colleagues to read about and learn more about. Let me finish, but love for you to have final comment.

Judd Moul: Well, I just want to say congratulations again on the EMBARK trial. It was a long undertaking and I want to thank the company sponsorship. It took a major commitment for the industry to be willing to stick out a trial that took this long. I think it was definitely worth it, but I remember at the beginning thinking to myself, I'll be retired before we get the answer to this trial. I'm delighted to say I'm still in practice and I'm going to try to put some of this trial information to my patient care. But again, as always, Dr. Shore, Neal, it's great to be with you today and discuss these papers. Thank you so much.

Neal Shore: Awesome. Thanks Judd.