Transcript:Raoul S. Concepcion, MD, FACS: Let’s move on and let’s talk about androgen receptor (AR) targeted therapy for nonmetastatic castration-resistant prostate cancer (CRPC). Judd, you had talked about this large population of what we call M0 disease. So it’s that CRPC patient that radiographically when you study them, and traditionally it’s been technetium bone scan or CT, that currently does not have metastatic disease.

So, Mike, if you look at the AUA Guidelines for M0 CRPC, that would be index patient 1 in the AUA Guidelines or if you go to NCCN M0, what are the current therapeutic options for M0 disease?

Michael Fabrizio, MD, FACS: So we have limited therapeutic options. I think that’s the amazing thing for us right now. Most of our drugs that we’ve just been talking about and will talk about are for patients who have metastatic castrate-resistant disease. So the M0 space is really completely wide open right now.

There are multiple clinical trials using some of the AR inhibitors that we’re looking at now. But hormonal therapy with androgen deprivation therapy is the mainstay. And that is even debatable as to when to begin it. Do you begin it when the PSA doubling time is less than 10 months? Do you do it when their absolute PSA is greater than 2? What is the factor?

If you poll 100 urologists in the United States, you’re going to get 99 different answers. And I think even medical oncologists defer to you guys. So we really have limited options in this space right now.

Raoul S. Concepcion, MD, FACS: So, basically, it’s observation or manipulation using existing anti-androgens, which do not have a documented survival benefit or a clinical trial. Now, there have been a couple of key trials that have been reported over the past year. Chuck, can you talk a little bit about IMAAGEN as well as STRIVE?

Charles J. Ryan, MD: Sure. So IMAAGEN is a nonrandomized study of early abiraterone with low-dose prednisone in patients with nonmetastatic CRPC. But the data basically demonstrate that virtually all patients will have some degree of PSA response.

The 50% decline rate in PSA was extremely high, in the 90% range. And, at this point in time, the study continues on and the median time to radiographic progression has not yet been reached. The median time to PSA progression is in the 25- to 26-month range, so very, very long duration of time. So that’s abiraterone, and I think notably it should be stated that this was abiraterone at 1000 mg with 5 mg daily of prednisone, so not the 5 twice a day that we commonly think of in the metastatic setting.

STRIVE is a study of enzalutamide comparing it to bicalutamide. And that was a study that included a CRPC and nonmetastatic CRPC component and essentially, at the current rate of reporting, the median PFS and median PSA progression have not yet been reached compared to bicalutamide. However, when it comes to the hazard ratio of comparing bicalutamide to enzalutamide, the hazard ratio is around 0.2, in that range. So it’s about an 80% improvement over bicalutamide in this setting in terms of delays and progression. That study is still developing.

Raoul S. Concepcion, MD, FACS: So, Judd, how do you think that plays for the urologists?

Judd W. Moul, MD, FACS: It’s really important for the urologists. We’re struggling and I have quite a few guys that I’m nursing along. They’ve been put on hormonal therapy for biochemical recurrence, and a decade ago I think we used hormonal therapy like candy for PSA recurrence. There were tons of patients who were put on hormone therapy irrespective of their risk group, and so now they’re coming to castrate-resistant disease and they still don’t have metastasis.

With regard to STRIVE, for example, one of my concerns is why did they use bicalutamide 50 as their control group. Many times if we’re trying something that we can use, we use Casodex or bicalutamide 150, which was the dose in the old Early Prostate Cancer (EPC) trials. I’ve had some experience using nilutamide. Urology residents don’t even know what that is, but that is a drug that can be used.

The challenge there is it’s quite expensive, even though it’s generic and it’s an old drug. Apparently only one company produces it, so it’s actually more difficult sometimes to get nilutamide in this setting. I wish we could use abiraterone, I wish we could use enzalutamide. The data is looking strong, but we can’t typically use it because it’s off-label.

Charles J. Ryan, MD: Which came first, the chicken or the egg question in CRPC is yes, these drugs, if they become available, we would use them and it would be good. We would be treating PSAs, so that’s one of the issues.

Michael Fabrizio, MD, FACS: Right.

Charles J. Ryan, MD: But the other issue is what happens at the back end.

Michael Fabrizio, MD, FACS: Receptor.

Charles J. Ryan, MD: If patients can live out the rest of their life to a normal life expectancy with their cancer controlled on enzalutamide or abiraterone, that would be a great thing. But if we produce a more virulent form of the disease at the point of resistance, that could be a problem. So we just don’t know that question.

Michael Fabrizio, MD, FACS: That’s a many years study. We’re upregulating those receptors. We know that we’re going to change the binding domains down the road. So, as you said, maybe we make a more lethal cancer.

Charles J. Ryan, MD: As much as I’m in favor of interim endpoints for clinical trials and support that it’s worth having that conversation, we still need to look at survival.

Michael Fabrizio, MD, FACS: Absolutely.

Jorge A. Garcia, MD, FACP: I think that’s the biggest challenge, Chuck, that when you look at the failure when we have developed clinical trials for CRPC in the M0 patient population is that. The gold standard for us for registration in this country remains survival, and so the question is if you’re able to delay radiographic progression, if you’re able to delay time to PSA progression, is that meaningful enough that it will become a surrogate marker for outcome, i.e., survival? And I don’t think we know that yet.

So, in the absence of that data, I think that we still don’t have treatment options for these patients, but more important than that, when you think about how we truly define M0 patients, I think all of us recognize the fact that M0 patients do have metastatic disease.

What happens is the technology that we’re using is not allowing us to detect that metastatic disease. We continue using technetium 99. Perhaps with better imaging techniques where you use choline PET or sodium fluoride PET, if you detect those patients early then the question is would timing really matter. If we put a patient on that trial, would you see that improvement in outcome? Because, as we talked earlier, those patients were not the patients included in the PREVAIL data. Those patients were not the patients who entered the COUGAR 302. So I think that’s a big question.

Charles J. Ryan, MD: I don’t look at it and say does this patient have metastatic disease or do they not have metastatic disease. They all have systemic disease and that’s really the crux of the issue for me. But, on the same token, if I’m a clinician making a decision about whether to treat a patient and I know the level 1 data we have with enzalutamide and with abiraterone has to do with patients who had technetium old school bone scan—positive disease, I know that I’m in the same ballpark as other clinicians and what the FDA approval is all about if I’m making a decision based on those old school techniques.

Transcript Edited for Clarity