FDA-approved Indications for Treatment Versus Use in Current Clinical Trials

Panelists: Raoul S. Concepcion, MD, FACS, The Comprehensive Prostate Center; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Alicia K. Morgans, MD, MPH, Vanderbilt University Medical Center; Ashley E. Ross, MD, PhD, Johns Hopkins Medical Institution; Daniel R. Saltzstein, MD, Urology San Antonio


Raoul S. Concepcion, MD:
I think it’s important for the viewers to understand that abiraterone acetate (Zytiga), enzalutamide (Xtandi), sipuleucel-T (Provenge), radium-223 (Xofigo), and cabazitaxel (Jevtana), their FDA approval is for patients with castration-resistant prostate cancer (CRPC)that have documented radiographic metastatic disease. Because we hear this all the time, we hear about people who are prescribing these drugs in the nonmetastatic (M0) radiographic patient and getting away with it, if you will, because, “Well, they really have microscopic metastatic disease.” And I think it’s really important for those of us who manage these patients to understand that the registry trials were for patients with metastatic radiographic disease. It wasn’t in the M0 patient. Now, again, I think we all know these newer imaging techniques will change this. Radiographically, what’s the significance of these lesions? We just don’t know.

Jorge A. Garcia, MD: Something interesting, Raoul, if I may interject for a second. If you look at actually the IMAAGEN data, the median time to PSA progression was around 28 months and the median time to objective progression was around 44 or 45 months. That means that there is a gap of around 1 year or more between your rising of PSA, however you define that rising in the trial, and when you develop progressive disease objectively. And, more importantly, I think we put a lot of weight on these oral agents even in the M1 CRPC space. Yes, you can lower PSA, and yes, you can reduce tumor size. But let me add in the survival improvement that we see with abiraterone or with enzalutamide in the metastatic castration-resistant disease. If I’m 55, I develop CRPC, and you’re going to tell me my median survival—median is actually 35 to 36 months compared with a placebo, which is 31 or 32—I think we have a lot of work to do because the reality of it is it’s still a median, it’s not a home-run for most patients. And, in fact, the vast majority of patients on abiraterone and enzalutamide are not those people who are driving the curves to the right. They’re actually people who actually stand there. Median progression, yes, is around 16 to 18 months, but the median survival is 3 years. And for you to tell a 55-year-old guy that you just operated on 1 year or 2 years ago, who developed CRPC, that abiraterone and enzalutamide are the best agents that we have in this space, it’s just hard.

Alicia K. Morgans, MD, MPH: I would agree with that, and I would say one of the best things about abiraterone and enzalutamide is that I believe we can safely combine them with other treatment modalities. I think that just as we’ve seen in other solid tumors, sometimes using other multiple approaches simultaneously may be the best way to ensure a more durable response. And so, I wonder how that may proceed. I do want to mention though, too, that I’m also hopeful that the NCI and the FDA are moving toward using metastasis-free survival as a possible clinically relevant endpoint. I think the ICECaP strategy, an approach that Chris Sweeney has put forth, has demonstrated, at least to me, that metastasis-free survival probably does correlate with overall survival very, very well. And I’m hopeful that will be something that will be able to move forward.

Just one final note to your other point: as medical oncologists, we love to get, again, back to side effects. And actually, I’m working right now to assess the cognitive function changes with enzalutamide because I love that drug, and I do think some patients tolerate it very well. I don’t know that they have many side effects, but there are some patients who seem to have profound fatigue that I believe is also coupled with a cognitive function issue. I think part of what we should do as medical oncologists, and as a field, is identify those patients who may be more susceptible to developing cognitive dysfunction. And if we can pick them out from the get-go, we may be able to direct our therapies more appropriately and maximize quality of life for all patients.

Ashley E. Ross, MD, PhD: Just to dovetail into that, one point that we were making in the first segment was, in most cases, try not to put your patients on this train, try not to start treating them, like you were saying, with ADT in the M0 hormone-sensitive states. You’re now treating them with second-line agents here. I’m also shocked, and I’m glad that you were studying it, because in the ADT, even away from the enzalutamide and abiraterone arms, about 20% of patients will have no side effect that they’ll ever report. It shocked me. And then on the other end of the spectrum, you’ll have severe side effects. The second point, just to go back to serial imaging: Dr. Garcia brought up the idea that when you’re putting people on abiraterone or enzalutamide now, instead of in the hormone-sensitive state, pushing toward castration resistance, you’re now pushing those castration-resistant people possibly toward a small cell or neuroendocrine or very dangerous phenotype. For me, I don’t do a lot of this, but I think that imaging at some kind of serial level might become more important in that M0 CRPC state because you can’t fully trust your PSA that’s going to be really so highly suppressed by these agents. And so, I just thought I’d get your thoughts on that.

Daniel R. Saltzstein, MD: I will add 2 points to that. I think we saw some recent data that says that 25% of the patients on enzalutamide will not have a PSA change, but they’ll end up showing metastatic or worsening radiographic progression. And so, I think you’re right. Are we creating a different phenotype that’s out there that we really want to be considering earlier or things like that? I know we’re not going to really address AR-V7, but I think that’s going to be important going forward. I think all of us that are in this space have dealt with the toxicities of both drugs. We’re participating in the REaCT trial, which is randomizing 50 guys to abiraterone and 50 to enzalutamide. The patient and the caregiver are coming in on a 1-month interval and at 2 months, to see exactly, to get an impression, of what the side effect profile is and to identify the neurotoxicity that we all think exists that really hasn’t been as well reported as I think we like. I would like to be able to identify ahead of time though. I like what you said, Alicia, because you don’t know which patient is going to have that side effect, who is going to be that 20% to 30% per se.

Jorge A. Garcia, MD: And there is an interest from the company who has enzalutamide to precisely assess those patients who develop neurocognitive dysfunction. But, at the same time, it is the rationale that our companies are using to develop the agents that do not cross the blood-brain barrier that much. It’s interesting because enzalutamide actually competes for fluoride channels and GABA receptors, and then ODM-201 doesn’t appear to do that. Apalutamide appears not to be that; it’s not as severe as we would see with enzalutamide. To your point about PSA and so forth, it is a double edge when we’re actually trying to remove ourselves from PSA and chasing PSA. We remind ourselves that when we look at, for instance, the PREVAIL and the COUGAR-302 data, we didn’t use PSA to make treatment decisions as to efficacy or lack thereof. We only say, “Okay, we’re going to capture your PSA, but we’re going to measure RPFS as a composite endpoint of symptoms or radiographic progression.”

And, to your point, if you look at the subset analysis, the patients who benefit truly from oral therapy are those who actually have PSA declines. Yet today, our guidelines would suggest that if you have someone who starts abiraterone or enzalutamide, you can continue even if their PSA is rising—which I fundamentally think is a huge mistake because what you’re doing is seeing the natural history of the disease in front of your eyes. And it may be that those patients may have a splice variance or not, I don’t know, but clearly there’s around 30% of patients who within the first 3 months—I usually do PSAs every 4 weeks for the first 3 months—actually do have a PSA decline. On the contrary, for those who don’t have a PSA decline and they’re doing well with ACE, then I capture PSA at 4 weeks later and at 12 weeks. And if by 12 weeks, your PSA has not declined, I stop therapy and move on because those patients, to me, biologically may be a splice variant or maybe not. But, clearly, those patients, in my hands, I don’t believe they’re going to benefit from oral therapy, and I certainly wouldn’t put them on a sequential maneuver either.

Transcript Edited for Clarity
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