New Approval for the Nonmetastatic CRPC Population - Episode 4
Jorge Garcia, MD:The adverse effect management of this class of agents, again, requires the skill sets of someone who understands how to manage CRPC [castration-resistant prostate cancer], and certainly how to manage the adverse effects of AR [androgen receptor] inhibitors. As I said before, most of us, in our busy practices, have our supportive staff actually call patients, talk to patients, and so forth. I think that the skin rash is something for which you may consider actually holding therapy and/or dose reducing, for instance, with apalutamide. Some people use topical steroids. I don’t think I have ever used them. With hypothyroidism, again, it’s required that you frequently check the patient with thyroid function testing, to figure out if the patient is developing hypothyroidism.
The neurocognitive issue is probably the biggest problem that we’re having, because we really underappreciate that adverse effect. We don’t know how to follow those patients. And more important than that, when you look at the adverse effects, for instance, of just the lack of testosterone alone, and the impact of low testosterone levels on cognitive function, it’s real. So I think in the community, we underappreciate those adverse effects.
Traditionally, we tend to hold therapy with enzalutamide or apalutamide, and tend to dose reduce from 160 mg to 120 mg in the case of enzalutamide, sometimes even to a second dose reduction to 80 mg. The same would apply for apalutamide, when you look at the dose reduction data.
In ARAMIS, if you look at the drug discontinuation rate, the incidence of drug discontinuation just by adverse effects was probably in the 8% to 9% range. This is very low compared with the SPARTAN and PROSPER data. You can dose reduce again, but I think that…I participated in the phase I data with darolutamide, and the dose reductions that we have in those trials probably echo and mimic what we have seen in the ARAMIS data.
Lastly, if you look at the ARAMIS data quality of life report that Dr Karim Fizazi, MD, PhD, recently published and presented on at one of our national meetings, the quality of life data are consistent with the adverse effect profile that has been reported with the agent.
The unique difference between the ARAMIS trial and the other trials is that understanding the chemical structure of darolutamide allows the group who helped develop the ARAMIS trial to feel comfortable including patients who were at risk for seizure activity. Obviously, we learned that the risk of seizure is real for enzalutamide and apalutamide. Again, clinically, I don’t think that is the No. 1 priority when I select agents that can delay MFS [metastasis-free survival], and possibly even impact survival in a positive manner. I think you have to balance the trade-offs of that benefit against the adverse effects. I think that the quality of life in the neurocognitive dysfunction is, perhaps, the most important difference between ARAMIS, SPARTAN, and PROSPER, recognizing that, for the first time, those patients who were at risk for seizure activity were not excluded from trials. This allowed the ARAMIS data to have the safety signal in favor of those patients who were at risk for any reason or another.
It does appear that the drug-drug interactions are a bit different with darolutamide when you compare it with the other 2 agents. I think that most of our patients are taking many medications. Most people are hypertensive, diabetic, or are taking aspirin, or what have you. I think it’s very important for us to minimize drug-drug interactions when we’re thinking of starting these agents.
I think that one of the unique differences between the ARAMIS data as well is that it appears that darolutamide has probably the least impact in those drug-drug interactions, although it does get metabolized through the pathway in the liver. So it’s not that it doesn’t have any interactions, it’s just that it appears to be lower, mathematically, compared with the other 2 agents. It’s very hard to compare across trials, but that does appear to be the case.
Transcript edited for clarity.