Case 1: Differences in AR-Targeted Therapy Adverse Events in nmCRPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Neal Shore, MD, FACS:Let me ask you this, and with the caveat that these were really beautifully done phase III global trials. Blinded, double-blinded, prospective. And so, we look at the AE [adverse event] profiles. The drugs have some differences, right? There are some molecular differences. The AE profiles, not in comparator studies, but they did show some different things. Let’s talk about that, and your sense of the differences in profiles, and how you would make a decision with your patients.

Alicia Morgans, MD:I think AEs are always going to be important when we choose drugs for the treatment of this disease. Since we have 3 options, we might as well have those conversations with patients, and certainly think about it among each other and ourselves, too. This patient was started on darolutamide. I have a feeling that probably had something to do with the AE profile, and also probably because of his history of seizures.

It’s really important for us to acknowledge that the PROSPER trial did not allow patients with a seizure history. I’m not certain about the SPARTAN trial. But the ARAMIS trial setting, darolutamide, very clearly included patients who had a seizure history. And the other thing I think about, in addition to AEs, and I’ll get there, is the drug-drug interactions that are so important for my patients who end up being older men who often have cardiovascular comorbidities and other issues. So I think about that in addition to AEs.

The AE profiles are really difficult to compare across trials, and I really want to hear everybody’s thoughts on this. We’ve seen some people try to do that, and I think there are definitely problems with that. But what we can do is look at the AEs as compared to the placebo arm in the trial. We saw that a couple of things stood out in the SPARTAN trial, maybe monitoring for hypothyroidism or the development of that over the course of treatment. And then there is some level of patients developing rash as well. Certainly, enzalutamide looked very similar in the PROSPER trial to what we have seen. There were some patients who developed seizure, I believe, as well as some patients who noted fatigue, which we know is potentially associated with enzalutamide.

In the darolutamide trial, it looked to me, especially when adjusted for time on exposure, that there was a relatively lower risk of [adverse] effects, although things like fatigue still happened. It didn’t seem to be much different than placebo. But I am always cautious to actually compare these AEs across trials. And again, I am eager to hear what your thoughts are on this.

Kenneth Kernen, MD:Well, and I think Neal said this, we’re blessed with these riches of all 3 drugs. That also gives us some ability to counsel patients. “If you have a history of seizures, or you have a history of ischemic heart disease, there are other things that we can do.” You don’t have to always just shoehorn someone in, or give them something that really exposes them. The other thing, as we talk to patients about, “Hey, these are your options,” is we can say, “If you experience this fatigue, or cardiovascular, or whatever, we have something else to move you to.” And I think that gives them great comfort as well. So we have all of these different options.

Jorge Garcia, MD:Let me be provocative. Can you just imagine me without a healthcare background coming to you, Neal, or you, Alicia, or you, Ken, and you talk to me about my state of disease? You tell me there are 3 oral agents. You’re still debating, between yourselves, which oral agent is the choice for me. The last thing that I want to even think is that this is controversial in the field, as to A, B, or C. So I actually, to be provocative, do not talk to my patients... I tell the patients there are 3 oral agents out there, and that I’m going to make the decision based upon their needs. I may have mentioned their names, but I don’t give the patients data about the 3 agents because I think it’s just way too much for a patient, to be honest with you, to process, in my opinion.

I think that also, let me pick on the CNS [central nervous system] toxicity and the seizure issue, specifically. When enzalutamide got approved in the AFFIRM data in the post-docetaxel space, and then moved into the PREVAIL data in the pre-chemotherapy space, we recognized the incidence of seizure was around 0.9%—less than 1%. So to look at the impact of outcome of these oral agents against the toxicity profile of having a seizure episode, to me, is meaningless. However, we now have data from the UPWARD study, which is Mike Morris, MD, and Susan Slovin, MD, PhD’s, data, that included patients at risk for seizure activity. The risk of seizure activity with enzalutamide was still no different than before.

So I’m not sure that seizures, for me, are the big distinction here. I think the neurocognitive dysfunction that I believe is underappreciated with enzalutamide is, perhaps, one of the biggest concerns that I have. AR [androgen receptors] inhibitors, and we know that from the high-dose bicalutamide era—the 1980s and 1990s—can lead to hypertension. So I think dollar for dollar, if you allow me to use that expression, hypertension, cardiovascular issues not only are related to a lack of testosterone but also to the AR inhibition.

I think the concern that I have with falls, fatigue, and neurocognitive dysfunction is real. I think there is a unique difference across the agents. You mentioned that, Alicia. You know, obviously with apalutamide, you have rash, hypothyroidism. Enzalutamide doesn’t do that. With darolutamide, you don’t have the rash. You have a bit less incidence of hypothyroidism. But because how darolutamide is structured, chemically, it doesn’t penetrate the brain barrier. It doesn’t compete for GABA [gamma-aminobutyric acid] receptors in the CNS. Therefore, you do see a distinct difference between the 3 oral agents.

I am a bit biased, and I know, Neal, you also participated on the darolutamide development. I think that I do see a significant difference, at least in my prior history with darolutamide. So when you look at that, I think that, yes, the seizure activity may actually skew you to apalutamide or darolutamide. But I think we have underappreciated the cognitive dysfunction that our patients develop. And I know, Alicia, through your interest in quality of life and PROs [patient-reported outcomes], we’ve been trying to push that—that we really don’t understand cognitive dysfunction that well. We don’t know how to measure it. We don’t know the baseline. Lack of ADT [androgen deprivation therapy], alone, can give you those adverse effects. I think it’s complex, but I do agree that most of us will actually end up selecting an agent based upon our comfort zone and the understanding of those adverse effects that have been presented in the trials. But I agree with you. There is a complexity in how you understand the 3 oral agents. I don’t want people to actually believe that you can compare across trials, because that cannot be done.

Neal Shore, MD, FACS:I love the provocative nature of how you began. Let me tell you where I think we’re going in the next months to years. We’re all starting to do this work. Alicia’s been pioneering this for quite a long time. You’re absolutely right. It’s the spectrum of neurocognitive dysfunction. It’s not just seizure.

Jorge Garcia, MD:Yeah.

Neal Shore, MD, FACS:Which, by the way, apalutamide and enzalutamide excluded, in their studies, patients with seizure. And darolutamide was interesting. Those patients, in early phase to phase III ARAMIS, had never been excluded.

Transcript edited for clarity.