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DR EISENBERGER: I would treat patients with nonmetastatic castrate-resistant. If some of these drugs would be available to me, I think that I would, particularly those who are progressing, clearly more than just a little bit, just a little smoldering PSA progression, I would consider them. In a trial, those who would have a PSA doubling time of less than 10 months, had a worse prognosis or a higher probability of developing metastatic disease. I would take a little bit of PSA doubling time and other PSA dynamics and value PSA as a guideline.

I do admit that we don’t have any data at this time.

DR LOVE: So Susan, a patient who says, “Cost is no issue. I’ll pay for the medicine,” PSA-only disease.

DR SLOVIN: I would do exactly what Mario would do. I would have no qualms about using it in a castrate metastatic without evidence of disease. But what that really brings to the attention is: What about those people with biochemical relapse or people who are at high risk of disease, relapse? Remember a number of years ago when bicalutamide was being pushed at 200 or 150 milligrams as a single pill, “Look what it can do for you,” I’m often wondering whether they’re going to try to do this as part of a trial at some point to look at people who are at high risk, so people who are, at the time of surgery, have metastatic disease to nodes or something that would indicate their disease will come back. Will this be considered as a single-agent adjuvant therapy?

DR DREICER: So I would answer that there are at least 6 trials in development soon to go that are going to do very similar things to what Dr Slovin suggested. My answer — I want to mitigate it a little bit. One is, I wouldn’t do that. The problem is: You have an expert panel talking about use of these compounds. The problem is that out in the real world, there are a lot of 78-year-old guys who are 13 years out from their prostatectomy who got treated with ADT, in my judgment inappropriately, for a slowly rising PSA, never going to die of disease. Now 5 years later have biochemical progression in the castrate setting. Never going to die of disease but are going to get these drugs because they hear people say, you know, so what they’re not hearing is the high-risk features of the folks that my colleagues are treating.

And the problem is, there are lot more of those than there are of these. And so I want to see data in the nonmetastatic patients. As the good Dr Smith pointed out, we have no idea about long-term exposure. And now we’re talking about the natural history of 5 and 8 and 10 and 12 and 13 years. And when are we going to stop these drugs? So I’m a little worried about a slippery slope here.

DR OH: I mean, I think the real issue is most of us understand we want to be data driven. But there’s a lot of places in medicine where there’s just no data to support it. Biologically it makes a lot of sense to take a 50-year-old man who has metastatic disease, early castration resistance, asymptomatic, maybe no metastatic disease, and consider adding a drug like enzalutamide to his primary hormonal therapy, but there’s just no evidence to tell us if that’s both safe and effective. So would I consider it in a setting like that that I just described? I think the patients bring it to us. They say, “If this drug works in the setting of metastatic castration-resistant disease, why wait, if you know that I’m going to become castration resistant in the very near future or even in a few years?” And I think that’s a compelling argument from their perspective.

I think the real issue is that until we have a broader safety profile, until we get out of the clinical trial and into the real world, until we, even as academic investigators, have more experience with this drug in various disease settings and various types of patients, it’s hard to make that recommendation off the bat. But over time I think people will certainly want to see the clinical trials but also have more comfort with the drugs.

DR SARTOR: Being in this data-free zone, we can just about do anything. But first thing is, going back to what Rob said, I think it’s absolutely true that a lot of people who just have a little slow rise, even the castrate resistant, they do not progress very rapidly. The data sets that Matthew has published on as being able to bring forth the certain criteria patients, PSA above X, doubling less than X, and it’s a little bit of a different subset of patients. So I might even introduce a concept that is totally weird and nondata supported, and that is intermittent use of these agents.

I worry a lot about the side effects of long-term extreme androgen deprivation. Sarcopenia, muscle weakness, it’s real. And when you get these patients who’ve been — particularly elderly — for a long period of time on extreme androgen deprivation, they’re showing effects of that androgen deprivation. They’re weaker. They’re fatigued. They’re not exercising as much. It’d be great if we could get them all to exercise. They don’t. They probably sit at the table and eat a little more. They gain a little more weight, exercise less. It’s not all good quality of life.

DR LOVE: Interesting. Tom? How low will you go?

DR BEER: I think I’d be very careful. I mean, first of all, as I think has been alluded to, I’d risk stratify these patients to make sure they need any kind of treatment, no matter what it is. And if I decided that they needed treatment, today I would still lean toward the agents that we’ve used before, like bicalutamide or even ketoconazole. I don’t know what the long-term side effects of these agents are.

I’m a little more worried about abiraterone, because the prednisone component becomes more and more, in my view, important. And we’re talking about 5 years of therapy in this setting, potentially. Enzalutamide may not have that issue, but we don’t know very much about the long-term side effects.

But here, again, we would be proposing potentially years and years of therapy. Is that 1% a year? I don't know. But that would become, I think, potentially important in a setting where the risk from the disease is pretty modest.

So the bottom line is: Today, I think I would be rather conservative about the use of these agents.

DR PETRYLAK: One of the reasons why combined androgen blockade did not initially pan out is we had very poor antiandrogens. Bicalutamide was really not an optimal antiandrogen. Same thing with flutamide. Same thing with nilutamide. Now we have better agents. And I think according to what has been said by Tom and Oliver and everybody else, is that we may see a greater spectrum of side effects with complete androgen blockade or complete shutdown.

Particularly, some of these studies have indicated neuropsychiatric changes over time. And they may not have been consistently reported, because the androgen blockade may not have been as complete as we’re seeing now. Same thing with seizures. Remember, too, that the average time that patients were on enzalutamide is about 6 months. You’re talking now about years on enzalutamide, which may actually change your spectrum of side effects. So I would be very, very cautious outside of a clinical trial.

DR SMITH: If we don’t like the long-term side effects of ADT, we may like the safety of long-term exposure to abiraterone and enzalutamide less. It’s a question that needs to be prospectively studied.

We can comfortably generalize from postchemo to prechemotherapy, because both groups of patients will almost certainly die of disease. Not the case as we move earlier and earlier in even high-risk non-metastatic CRPC. The median survival is 4 or 5 years. Many of those deaths are unrelated to cancer. And what we’ve learned from the NCIC Protocol 7 trial is that the majority of patients with PSA-only failure after radiation or surgery die of other causes. So we really have to be very careful about understanding these competing risks.

I would not comfortably generalize the data in metastatic CRPC to nonmetastatic disease or even earlier, except in perhaps the unusual case. And then this, again, mirrors Rob Dreicer’s comment. Those are the exceptions and not the rules.