Neal Shore: Thanks, Phil. Great to be with you.
Phillip Koo: So localized prostate cancer is something obviously we're all familiar with. I would say the diagnosis of localized cancer perhaps has evolved over the past few years, especially with the introduction and increased use of PSMA PET. So what are your thoughts a little bit about how that space has changed with better imaging?
Neal Shore: Yeah, it's been pretty remarkable. So back in the arc of my career, you did a digital rectal exam and then we started getting into pioneering work by Kooner and Lee on just better quality visualization with ultrasound. And I think urologists really started to pick up and understand that importance. And we've gone from low-frequency to high-frequency ultrasounds. And then of course the burgeoning of MRI, which has been exceptional. Our understanding of the anatomy, the architecture, high-risk, low-risk areas, PI-RADS scoring, et cetera. And then now PSMA PET. So a lot of really interesting and dynamic work going on with PSMA PET, how to correlate it with MRI. And then I think also to your point, how do we better risk stratify not only who to biopsy or not to biopsy, but then when we get histopathology, how can we better do treatment selection?
Phillip Koo: So it's great, we have better information leading up to now this decision point where we have to select a treatment. And the treatments often focus on surgery and radiation. What are your just high-level thoughts on efficacy and sort of patient perspectives on how you choose what type of treatment? Definitive treatment.
Neal Shore: Yeah. I mean, there's a lot of really fun and enjoyable, interesting work many of us are doing in what are called discrete choice experimentation, sort of understanding what are patient preferences, who is more on the risk-averse versus risk-seeking, and what will different therapeutics or active interventions sometimes it's called, whether it's radiation from externally or our brachytherapy. Focal therapies, a whole clearly over the last several decades has been burgeoning. Not a tremendous amount of level I evidence on the focal therapy, but it's become very popular. And then of course, classic prostatectomy. I think when you get to the question about what do patients want, we've really learned a lot more in the last few years of having a better conversation. So we have what's we oftentimes called shared decision-making. So what does it mean to have testosterone suppression and androgen deprivation therapy if you're going to have radiation treatment? A lot of studies are out there now trying to figure out how do we optimize different systemic therapies and even potentially injectable therapies into the prostate if we're choosing not only radiation, but even arguably perioperative strategies around prostatectomy and even some folks with focal therapy. And let's of course not forget some patients don't really need anything done, but active surveillance.
Phillip Koo: So that's really interesting. I think the decision, when they approach that decision, that fork in the road, I think there's so many different options. And then you're also dealing with conversations about ADT. And I think what we're realizing ADT is not just something so benign, and a lot of considerations there. And patients might have a lot of questions and confusions and concerns around that space. Can you walk us through what they might be thinking about how you add ADT and how long?
Neal Shore: Yeah, I really appreciate that. Look, started my career most of my first clinical research was all in various depot formulations for ADT, agonists, antagonists, parenteral, subQ, IM, oral. And you're absolutely right. I mean, there is no free lunch with testosterone suppression. I think here more and more now, despite all the homage we pay to the phenomenal work of Huggins and Hodges, almost every article in prostate cancer is typically beginning with, "And the bedrock and the foundation and the mainstay is ADT." And I think many of us are starting to say "Now, well, wow, wouldn't it be nice if we could minimize or potentially completely obviate or relegate to the back burner testosterone suppression?" Because patients really, they let us know. I mean, they don't feel as well. I rarely met a patient who said, "Well, I feel better since I started my ADT." We're starting to learn more about the cardio-oncologic implications, the neuro-oncologic, in addition to the well-described fatigue, sometimes some cognitive changes, but clearly the sexual dysfunction, the hot flashes. Patients who've experienced ADT oftentimes will be like, "I'll go and try another therapy if I indeed need something, but can we just please avoid that?" And I see that across the board, generational, all different demographics. So when it comes to localized therapy, particularly in the field of radiation and even perioperative strategies now to try to enhance and avoid surgical recurrence, whether it's BCR or local recurrence in prostate with radiation, I think patients are extremely open to other alternative strategies.
Phillip Koo: That's fascinating how this has all evolved. And I love how patients are helping direct where we're heading as a field. So it's fascinating to think about how all this prep work, you make a decision, you undergo a definitive curative treatment, patients are excited, they're hoping it never recurs. But unfortunately we know it recurs at a pretty high rate. Can you walk us through what you're seeing there why we have such a high recurrence rate?
Neal Shore: Yeah, that's a good point. Well, of course, if you're a surgical oncologist or a radiation oncologist, and hopefully everybody's working in a really tight, multidisciplinary way, you want to think that we never have failures, but of course we do. And depending upon the category, the grade group, and maybe the absolute PSA, the volume of disease on histopathology, we see typically 20 to 30% failure rates. And so there's obviously an unmet need to how we can do better while at the same time trying to minimize the voiding and the sexual adverse events that typically happen occasionally rectal. And there are maybe some other less common but real systemic effects. So there's an unmet need. We're not 100% successful and nowhere close with our current level I evidence radiation strategies, whether they're combined with brachy, external beam, as well as with prostatectomy.
Phillip Koo: So I think it's really exciting to see that there's a lot of hope in the future. And at least in my career, I remember there was so much attention in CRPC, hormone-sensitive. Now with BCR, you led the EMBARK trial. And now we're seeing a lot of new innovative ideas in the localized space. So can you sort of just give us a high-level roadmap of what you're seeing that might come down the pipeline?
Neal Shore: Yeah, there's a lot of things, and it's super exciting. How do we do better in terms of our active interventions, call it radiation therapy, surgical extirpation, prostatectomy. And there are many other iterations, especially on the focal side of things. So what's coming down the pipe? I think we're going to start to see... Because the prostate lends itself so well to either a transperineal or a transrectal approach of injectables, placement of drugs that can augment potentially the synergy with radiation, and potentially avoid or decrease the amount of testosterone suppression. Wouldn't that be great to a therapeutic that could enhance biopsy-free recurrence, that could enhance the issue of BCR, and certainly enhance later on distant metastatic sites. And likewise, there are some radiopharmaceutical strategies that are being sort of tailored to the diagnostic component. Can we get PSMA, various PET strategies, different tracers that are out there, whether they're gallium, fluorinated or copper? Other ones that are probably coming, correlate that with MR or maybe not. And then think about a theranostic that could be given that's powerful, maybe only one or two doses that could be given in combination with or without maybe an androgen receptor pathway inhibitor where we wouldn't have to invoke testosterone suppression. It's been one of the fun and enjoyable things from the EMBARK trial is that we did have that third arm for the BCR patients who actually did remarkably well with just enzalutamide monotherapy. So I think we're still learning a lot more. And I think it's for our colleagues who treat localized prostate cancer, much like with systemic metastatic disease, whether it's sensitive or resistant, a lot of great studies that are going to be ongoing now and will read out in the next couple of years.
Phillip Koo: I think this is so exciting and provides so much hope for providers and for patients, more efficacious interventions and improved quality of life. So thank you so much for setting the stage on what localized disease is and what it might look like in the future.
Neal Shore: Great. Thanks, Phil.