Clinical Trials in Nonmetastatic Castration-Resistant Prostate Cancer

Transcript:Raoul S. Concepcion, MD: Recap for us. What trials are out there that you’re aware of or that you’re even participating in for that true nonmetastatic (M0) patient?

Ashley E. Ross, MD, PhD: For castration-resistant prostate cancer (CRPC), M0?

Raoul S. Concepcion, MD: For M0 CRPC.

Ashley E. Ross, MD, PhD: There are a few out there. And one thing—just to elaborate on the point and just about which reader is reading things—in the recent IMAAGEN trial, which is looking at abiraterone in this state, Crawford put out a paper just on the screening of the cohort. I think it was something like 30% or so that were actually found to have metastatic disease. And that, to me, just meant that having a dedicated reader of these scans or being more meticulous about it would identify them. But there are trials like that one that are looking at abiraterone. And then there’s the PROSPER study that looks at enzalutamide, enzalutamide being the triple-action drug, inhibiting to the nucleus, binding to the AREs. There are 2 newer drugs that are being evaluated: ARN-509 and ODM-201. Those are in the SPARTAN trial and the ARAMIS trial, respectively. My impression, and I’ll defer to our medical oncologists, is that enzalutamide has a small signal of seizure risk, probably because it passed the blood-brain barrier. The Bayer drug, the ODM-201, I think has no ability to do that at all, and the thought is that it would have less chance of causing that side effect.

In general, with the data that are already coming out of some of these trials, it looks like the toxicity of the agents is similar to what you would have in the metastatic space. To me, it’s a little bit concerning in some ways because, for example, for enzalutamide, although it’s fairly well tolerated, some patients can have really severe fatigue. We talk about the trade-offs, and certainly for patients who have or may be prone to a seizure disorder, you want to avoid that. Me, I would defer to our medical oncologists to see what they think is going to be the best agent for this space because I think the drugs look fairly similar. They all should be evaluated. My overarching thought is that we have to move toward do we think we can be curative in this space? Is there a chance there? And maybe with these androgen blockades, it may come down the road with an immunotherapy. I’m not sure.

Raoul S. Concepcion, MD: Alicia, are you comfortable talking about IMAAGEN?

Alicia K. Morgans, MD, MPH: Sure.

Raoul S. Concepcion, MD: Okay. I just want to make sure. I don’t want to put anybody on the spot here. So, I think that’s right. I think there is this interest by all the manufacturers and all the pharma companies to really move these agents that clearly, in monotherapy trials and in metastatic CRPC patients, have a survival benefit. We know that Janssen did IMAAGEN, which was a phase II trial. I think Charles Ryan reported this out at ASCO. We know that that was 1000 mg of abiraterone acetate, but given with just 5 mg of prednisone. Is that correct?

Alicia K. Morgans, MD, MPH: Yes, it is. I think understanding that that’s safe is actually really important, particularly because this was in the M0 space. We wanted to try to limit the side effects of higher doses of prednisone if we could. And it did appear that there’s a PSA progression, maybe a delay. I think my concern with the trial is that there wasn’t necessarily a control arm on this trial. But it did show that it was safe, at least, to do this; it was safe to do it in the M0 space. And there’s hope, then, to continue the studies that are ongoing and really try to further our understanding of whether this should be inserted in the M0 space. But more than that, I don’t know what we can say from the IMAAGEN trial. But, as Ash said, I think it was striking that so many of the patients that clinicians thought were M0 to enter into the study were actually not M0 when reviewed for their true eligibility for the trial. In this small space, M0 CRPC may be a fleeting space that ultimately may be very challenging in which to find therapeutics directed specifically to those patients.

Raoul S. Concepcion, MD: Dan, the pushback from urology about very small doses of prednisone that we use with abiraterone—which I think for you and I that treat a lot of these patients, it’s not that big of a deal—are you surprised at the pushback that comes from our colleagues with the addition of a little bit of prednisone?

Daniel R. Saltzstein, MD: Absolutely. Again, I think we’re trained that to cut is to cure, and so we have a different mentality than the medical oncologist. But I think it’s like being comfortable with giving BCG or any of the agents that we know. Once you get a familiarity level with a certain product, you get over that hump. Again, we’re only using physiological doses. We’re only replacing what the body would normally give. We’re not giving the same dose you give to somebody with bad arthritis or a bad injury or something like that. We’re only giving the physiological dose. Again, it’s an uphill battle, like introducing any new drugs into a space, but it’s very easy to manage.

Raoul S. Concepcion, MD: Jorge?

Jorge A. Garcia, MD: So, when I think of the M0 space, I think that the 2 biggest challenges of this space are: first, how do you meet clinical endpoints with registration strategies? We don’t know if reducing your PSA or delaying radiographic progression-free survival (RPFS) can be utilized as a surrogate marker for outcome for survival. To this day, to the FDA registration agency, survival remains the gold standard for FDA approval. So, that’s one of the challenges. The STRIDE trial, which captured around 30% of patients with M0 disease, clearly demonstrates a striking delay in RPFS almost by 80% compared with patients who were randomized to bicalutamide in that M0 space. IMAAGEN, as Alicia mentioned, also did the same. It showed not only 90% plus PSA reductions, but also in that delaying in RPFS at the time, when Chuck actually presented that data, the median hadn’t actually been reached for those patients on IMAAGEN. Clinical trial endpoints are a big issue in that space. Now, whether or not enzalutamide is better than apalutamide, which is the former ARN-509 or ODM, remains to be defined.

I do want to remind all of us that abiraterone, outside of steroids, is a toxic agent and enzalutamide is a toxic agent. Not only is there fatigue, but the neurocognitive dysfunction that you see with enzalutamide-treated patients is significant. And I remind you that we’re moving these agents to the adjuvant space, to the pre-op space. So, these agents do have a lot of side effects. There is also the biological concern that the early introduction of these agents, maybe in AbiCure—and so far, you’re actually simply basically unleashing those cells, if I’m allowed to use that expression—really are going to become aggressive, and nothing is going to be able to control those phenotypes of cells, if you will. I think that the other challenge the SPARTAN, ARAMIS, and the apalutamide trials are facing is that it’s very difficult to randomize patients to an agent that is already FDA-approved that has shown survival benefit, PSA reduction, or tumor recist-defined response or response to a placebo. It’s a very hard discussion with the patient because of IMAAGEN, because of that fraction of STRIDE patients. There are a lot of people out there. I don’t know how they do it, but they do get coverage for enzalutamide or abiraterone in the M0 space.

To your point, I predicted, and I was wrong, that urologists will love enzalutamide. Why? Because it’s far more powerful, less agonistic, more expensive perhaps than bicalutamide. But there’s a lot of people in the community who use monotherapy. I’m hoping with the STRIDE trial that that monotherapy used in the M0 space is going to hopefully change. Whether or not starting enzalutamide or abiraterone in the M0 space is the right strategy right now, I’m not sure. I actually do not do it, but I don’t think it’s unreasonable to use it with the data that we have.

Transcript Edited for Clarity