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Rana McKay: Hi. I'm Rana McKay, and I'm so excited to be here on UroToday setting the stage of how we came to be where we are in 2023 and 2024 in prostate cancer treatment: where we have been in prostate cancer treatment, and where we are now. This is the first module in a series of 10 of this educational program on prostate cancer treatment. Today it is my absolute honor to present Dr. Neal Shore, who will be discussing an overview of localized disease. Neal?

Neal Shore: Thanks, Rana. What a great pleasure to be with you. Right, I'm going to talk briefly about the treatment intensification for high-risk localized prostate cancer. Of course, our low-risk localized prostate cancer, many of these patients are benefiting from just a strident active surveillance, but it's the high-risk patients who are the challenge.

So, we have a lot of different ways of approaching this. There's of course radiation therapy, there's surgery. That's really what I'm going to kind of focus on. But what are the neoadjuvant, adjuvant strategies? How do we think about using endocrine therapies, essentially T suppression? Will there be other therapies to augment endocrine strategies, AR pathway blockers? And then of course, what are some of the other things that we think about AI, artificial intelligence, genomic classification, hereditary risk factors with genetic investigation?

A lot of great work has been done on combining androgen deprivation therapy with radiation. And we know based upon the work by Bolla in Italy and Widmark in Scandinavian countries, that clearly there's a synergy. You enhance the radiation tumoricidal effect by having T suppression. And ultimately, we've gone from three years. Some will still offer that based upon the Bolla data. We've looked at two years, 18 months, 12 months, but ultimately at the end of the day, we want to get it just right. So that Goldilocks phenomenon of not too extreme, not too little, but just right, and we still sort of debate the optimal choice.

So we have various trials that support ADT for some patients and some patients, frankly, we don't necessarily need to do T suppression. That's where maybe the molecular classifiers and AI are going to come into play. I'm going to talk a little bit more about that. And then of course, there are patients that will clearly benefit from T suppression, the RTOG 16, the sports studies are really kind of different ends of the spectrum of thinking about that.

And just a quick mention, we talk about PEACE-1 and PEACE-3, but PEACE-2 is an important study looking at taxanes and pelvic radiation patients with high-risk localized prostate cancer. And fortunately, this large phase 3 trial has read out. Here's the study schema, and we certainly look forward to seeing that. We've had a lot of trials. I've been part of them using docetaxel in high-risk localized prostate cancer, and none of those have demonstrated any evidence for using docetaxel as a neo, really more of an adjuvant strategy. But we're still trying to see if a taxane regimen could be effective.

That moves us into STAMPEDE, and congratulations once again to our UK and Swiss colleagues who do STAMPEDE. And essentially, it's a little bit of a complicated schema, but hats off to them. A lot of patients, they had amendments in their study. They started this years ago, got close to really almost 2,000 patients, but at the end of the day really investigated ADT plus or minus enzalutamide with abiraterone versus radiation of course for high-risk patients versus ADT and radiation therapy. So really adding one AR pathway drug or AR-targeted agent or two.

And at the end of the day, what was really important about this study, a very nice paper published by Gerhardt Attard in The Lancet, he presented it at ESMO, I believe, in the same year, that there was an improvement in progression-free survival, metastasis-free survival, and overall survival with the addition of abiraterone and prednisone. The classic indication in MCRPC and MHSPC for the very high-risk population. You see the curve separating very nicely here. This is level one evidence, and now it's been incorporated into guidelines.

And this was the rectangular box highlighting the inclusion criteria. Pretty stringent. And some of us may loosen it, maybe less than 40, may not or greater than 40. You might broaden it to less than 40. But nonetheless, these were grade group four/five patients and potentially with nodal disease and with a high risk of relapse who receive radiation ADT and clearly adding abiraterone acetate is advantageous.

So this has now been incorporated into the guidelines. You see the ever-present large blue ellipse, which lets you realize that this is now part of the treatment pathway. So where does that leave us? Well, we have several other really important studies now, of course, kind of mimicking and trying to corroborate the STAMPEDE study. And here's one I'm very proud to be part of. We enrolled in this. This is now completely accrued. This is the ATLAS trial, which essentially now is looking at very high-risk patients who are going to undergo radiation therapy and to receive ADT and a placebo.

There's some lead-in with bicalutamide, but more importantly, it's an ADT radiation placebo versus ADT apalutamide. And I look forward to this. I think I'm optimistic based upon STAMPEDE, but that's why you do these studies. A very similar study, but instead of using apalutamide is using enzalutamide in the ENZARAD trial. And this trial has also completed accrual and will read out. I think these two studies will hopefully read out sometime in 2025. There's the DASL-HiCaP study, which is doing somewhat of a similar study with darolutamide. So I think it's a really interesting time.

So getting back to what I was saying earlier, how do we select to use ADT or not? Well, we've had molecular classifiers for a long time. We look at, of course, the grade group score. We look at PSA doubling times, but then we also can look at molecular tests such as the Decipher, which are oftentimes predictive of response.

And we have other genomic classifiers as well. But what's really kind of gotten a lot of headway that back to back, year after year plenary presentations at ASCO GU is now the use of artificial intelligence. And here's the Artera AI to predict in intermediate-risk patients, whether or not you need to give ADT or hold back. Primarily really tremendous amount of work looking at five different NRG trials. Look at the training set to develop the deep machine learning for their AI predictor. Then they call this the MMAI or a multimodal artificial intelligence really to try and delineate can we get away from six months of ADT or not? And this was really wonderful work presented by Felix Feng, Dan Spratt, and ultimately published in Nature and a great publication also in the New England Journal. So ultimately, this is, if you're AI biomarker negative versus positive, you can inform patients on, "Okay, this AI test is saying you don't need to undergo six months of testosterone suppression."

And I think everybody would agree if we can have validated tests such as this, which is now, by the way, and very interestingly incorporated into the NCCN guidelines and Medicare CMS covered in the US. So it's both prognostic and predictive, which I think is really kudos to the investigators who got this across the finish line. And quickly wrapping up, we're going to be presenting some very interesting data. We just completed an adjuvant study in high-risk localized patients, a little over a hundred patients, 28 sites in the US. We accrued this super quickly, very high-risk patients who were undergoing prostatectomy. It's an open-label, a hundred-plus patients study, and everyone got 12 months of ADT apalutamide. They had to have had a PSA of less than 0.2 at six weeks.

Now we know that this very high-risk group has a 20 to 50% likelihood of biochemical recurrence, and we're going to hopefully be able to present the two-year follow-up inclusive of PSA levels as T recovery levels. Remember, they're only going to receive these patients ADT and APA for one year. I'm super excited about those results and hopefully, we'll be able to present this later this year or this spring, I should say, in 2024.

And on the heels of that study is an ongoing trial called the PROTEUS trial. This is a phase 3 trial looking at six months of neoadjuvant ADT APA versus ADT placebo radical prostatectomy, followed by six months of ADT APA versus ADT placebo. Again, we have challenges in RP and RT in patients who are very high risk with a high failure rate, 20 to 50%, depending upon the analysis that you're looking at. You can see the co-primary endpoints here listed here are PCR. So the pathological complete response on the RP specimen as well as metastasis-free survival.

So a lot going on in high-risk localized prostate cancer. It's no longer your mom and pop just extirpative removal of the prostate or just basic radiation, but more nuanced around with radiation, certainly the duration of RT and adding or not an androgen receptor targeted agent. So at the end of the day, for radiation patients who are at high risk, ADT is foundational. We're still working through that process with our RP patients, adding an androgen receptor pathway inhibitor. Clearly, STAMPEDE tells us it's a new standard of care. Will we see corroborative data from other phase 3 trials? Well, it's wait and see. And then AI. Bam, it's here now. And I think we'll start to see even other important indications throughout medicine, but certainly throughout oncology and GU oncology as well. But we already have one now approved and in the guidelines for decision-making regarding intermediate-risk patients undergoing RT and for consideration or not of T suppression. So thanks very much.

Rana McKay: Thank you so much, Neal, for that outstanding overview of just where we are and honestly where we're going. There's a lot of really exciting trials that are going to change the paradigm in the localized setting. When I think about those men undergoing radical prostatectomy or electing radical prostatectomy as their primary modality upfront, we really haven't changed the strategy for those individuals over the last 30, 40 years. It's still just upfront radical prostatectomy. We haven't integrated pre-op or post-op therapy. And so I think there's a lot of really important studies that are looking at how do we intensify therapy for those high-risk individuals perioperatively that elect surgery, potentially sparing them the risk of recurrence, the risk of downstream radiation, and other side effects. And also, obviously, we've certainly made headways with regards to escalating for those high-risk individuals with ARSIs receiving radiation. You know?

Neal Shore: Yeah, absolutely. We've had great advances, of course, with imaging with mpMRI. We're getting additional fascinating imaging advances with PSMA PET. Our technique for RP, our technique for RT, has clearly improved, but we still have a high failure rate, so I really am excited about where we've moved in the field, and it is a fascinating, somewhat of a conundrum in prostate cancer, maybe more than almost any other solid tumor because we still have many patients with localized disease who we say, "Oh, you're low risk." We're still going to... Active surveillance is still a good call. So it's really fascinating. I'm so impressed by all the different investigators globally and how a lot of the societies and in a multidisciplinary way, bringing in medical oncology and radiation oncology with urology and nuke med, we're doing much better for our patients.

Rana McKay: I know. It's absolutely fantastic. I do believe that our patients are living longer because of the advanced therapies that have been implemented across their treatment.

Well, thank you so much for joining us on UroToday.