Transcript:Raoul S. Concepcion, MD, FACS: Mike, one of the things we hear is there is a requirement for a little bit of corticosteroids because of abiraterone acetate’s mechanistic actions. We hear this all the time from especially the community urologists who say, I don’t want to give abiraterone. I don’t want to have to deal with steroids. You’ve taken care of a number of these patients. You’ve used the drugs. What’s your response to that from a urologist who’s managing these patients?

Michael Fabrizio, MD, FACS: We basically tell the urologists we’re cutting off the entire steroid production high up on the pathway, and our body produces 7-1/2 mg or so of steroids a day and essentially that’s what you’re giving back to them. And so you really shouldn’t fear that. I think the long-term data is very clear now.

These patients take the drug for a long period of time, greater than 17 months, they tolerate it well, and the risk of steroids while present at any level is low in this patient population. They seem to tolerate it fairly well. You may see some alterations in their blood sugar. That may be one of the more common things you see, especially in the population we’re dealing with, but, in general, it’s well tolerated.

Raoul S. Concepcion, MD, FACS: For your particular clinic, because we know the monitoring is a little bit more intensive for abiraterone but nothing that’s too onerous, are you getting pushback from your patients in terms of them having to come in and monitor their potassium, their transaminases, those types of things?

Michael Fabrizio, MD, FACS: You get a little pushback, especially if they’ve been normal every two weeks for the first month or month-and-a-half and then they just stop showing up instead of going through the three-month period. And that’s when we have a nurse navigator calling them on the phone maybe a week later to say, hey, you better come in and get your labs.

But, really, it’s a fairly easy process to monitor these patients. You make it automatic right at the beginning. They come in. We typically see the changes and the alterations in liver function test. I’d be interested in the rest of the panel in the first four to six weeks of therapy, but not a lot of pushback.

Jorge A. Garcia, MD, FACP: I think in my practice, if I may add, we all practice differently in many ways. We follow the data obviously, but what happens in clinical trials is sometimes hard to translate into clinical practice. So, for instance, if you look at the data with PREVAIL and the data with the COUGAR 302, while the PSA was captured, it was never utilized to make decisions as to treatment failure or efficacy because the primary endpoint of these two trials was a composite endpoint between radiographic progression-free survival [RPFS] and survival.

So I fundamentally have an issue with that because I really believe these agents that target androgen receptor (AR) MUST, with a big capital MUST, lower your PSA. So I personally do this. I start the patient. Once I make that choice, which is unclear how to make it, but once I make that choice as to do you start abiraterone or do you start enzalutamide, then I’ll bring my patients the first four weeks. In that four-week visit, I want to see your side effects, I want to check your labs, and I want to see your PSA.

So, if you’re doing well clinically, you’re not having major side effects and your PSA is going down, then from then on I’ll match your appointment to the three-month injections. On the contrary, if they’re doing well, they’re not having side effects, they’re doing clinically well but their PSA is rising, then I tell them I want to check your PSA again in one month.

I want to see what that PSA does. I’ll bring you back. And if within the first three months I don’t see a PSA decline, in my practice I stop and abort any of those oral treatments and move forward because I don’t believe those patients will benefit from these compounds, even though the level 1 evidence, phase III data would suggest that you’re allowed to continue a patient on that therapy until they develop radiographic progression. For me, I personally think that just simply seeing the natural history of their disease progressing in your face without actually active therapy.

Charles J. Ryan, MD: Can I just point out then? In the 302 study, the patients who had no PSA decline had a survival that was basically the same as the TAX 327 patients, about 18 months. And so those patients probably aren’t benefitting at all. I do the same thing. I typically go 12 weeks. If I haven’t seen a PSA decline at all, they’re off the therapy and on to something else. And, actually, we now know that these might be the patients with the V7.

Jorge A. Garcia, MD, FACP: Exactly.

Charles J. Ryan, MD: And, in fact, it sort of raises the question of do we do a therapy to trial to just see where they are? There’s not a lot of harm done I think in eight weeks of a therapy if you’re starting somebody reasonably early. It’s almost like doing a clinical test of abiraterone or enzalutamide may prevent the need for the V7.

Jorge A. Garcia, MD, FACP: But to me, that actually contradicts, Chuck, exactly everything that we have tried to do over the last 10 years.

Charles J. Ryan, MD: I agree.

Jorge A. Garcia, MD, FACP: PSA is not the best tool but we measure their PSA. Yet we know that the level 1 evidence was one way but we practice in a different way because we realize the importance of PSA reduction in the context of these oral therapies. It is different when you see a patient that has a PSA decline and over time, the PSA starts to rise, and those are the patients that are much more challenging for us to manage.

Judd W. Moul, MD, FACS: Can I just ask both of you a practical question for the urologists listening in? So did I hear you correctly say you get a PSA at four weeks, and if there’s no PSA response, you switch gears at the four-week point?

Charles J. Ryan, MD: I usually do 12 weeks.

Judd W. Moul, MD, FACS: Both of you do the 12 weeks.

Jorge A. Garcia, MD, FACP: I do monthly PSAs for the first three months for those patients who don’t have a PSA decline because I want to see the change over time. Sometimes what you see, you see a PSA that goes up within the first four weeks and that’s what we in San Francisco called the broken arrow. The PSA goes up and then goes down. So we want to make sure that we capture those patients because it would be a mistake for us to stop therapy for those patients.

So, at four weeks, if your PSA is going up, I’ll give you an extra four weeks just to make sure then that PSA is not really actually going down. And sometimes you see 20% to 30% of patients who have PSA declines. However, if at that eight-week mark your PSA continues to rise, then I’ll tell the patient, you more than likely are not going to respond to this oral therapy. We’re going to see you in four weeks, and if your PSA at that four-week mark, at 12 weeks, is again rising, we stop therapy.

Charles J. Ryan, MD: Well put.

Raoul S. Concepcion, MD, FACS: So, basically, what you’re describing is a primary resistance.

Jorge A. Garcia, MD, FACP: Exactly.

Raoul S. Concepcion, MD, FACS: Versus the acquired secondary resistance.

Jorge A. Garcia, MD, FACP: Exactly.

Raoul S. Concepcion, MD, FACS: So, Chuck, you briefly mentioned 302. Tell us what COUGAR 302 is because you’ve reported on some recent updated analysis of that data, right?

Charles J. Ryan, MD: Right. We’ve published the final analysis of 302 earlier this year in Lancet Oncology, and as many people are aware, this was a randomized trial of abiraterone plus prednisone versus placebo plus prednisone. I think the key point was this was the first phase III trial that tested this chemotherapy-naive patient population that looked at survival with this type of drug. And so the study went through a number of interim analyses.

The second interim analysis was reported a couple of years ago and published. And with the final analysis, the vast majority of the patients have passed away at this point and it allows a fuller appreciation of the survival. The headline is basically the median survival for these patients was about 35 months. The hazard ratio compared to the placebo arm was about 0.81, so about a 20% improvement in survival.

There was a huge amount of crossover. Forty-four percent of the patients who were allocated to the placebo arm actually received abiraterone at some point in their life after study therapy. And so those are the key points. But there are many other subtler points that may be helpful for the practicing physician. So number 1 is there’s a 10- month delay, for example, in the need for opiate analgesics.

So, when I talk about the benefits of treating early in this setting, and I use this term with patients, I talk about the three Ps: preserve quality of life, prevent complications and progression, and prolong life. And that resonates with what patients want to get out of therapy. And, basically, the 302 showed that there was a statistically significant delay in the time to perform status deterioration, so preservation of quality of life.

There was a significant decline in the bone events. Fred Saad has reported on that. And we know the survival data now. So I think that that encapsulates the clinical benefit of abiraterone in this chemotherapy- naive patient population.

Transcript Edited for Clarity