Nonmetastatic CRPC: Treatment Selection

Alicia K. Morgans, MD, MPH: One of the things that’s a little different between these agents is their structure. Apalutamide and enzalutamide have a relatively similar structure. Both appear to cross the blood-brain barrier a little more frequently than darolutamide, which has a slightly distinct structure from the other 2. Sandy, in your experience, does that make a difference in your decision-making? Do you think the AEs [adverse effects] are any different? What are your thoughts?

Sandy Srinivas, MD: At least from the patients in whom I’ve used it in, darolutamide is better tolerated. There isn’t cognitive dysfunction. At least from the clinical trial point of view, there were fewer fractures and falls. In real life, it’s better tolerated compared with apalutamide or enzalutamide. That’s where perhaps this imaging becomes an issue, because if you look at those drugs, enzalutamide has approval across the entire spectrum, so it doesn’t matter if somebody has PET [positron emission tomography] imaging that’s positive if you’re going to treat them with an AR [androgen receptor]-targeted drug. But if you get into the nitty-gritty of drug approval and third-party payers, darolutamide is only approved in the nonmetastatic setting. Like Scott, I also use this to see how it fits. If I use conventional imaging and it’s negative, I advocate darolutamide for those patients.

Alicia K. Morgans, MD, MPH: That’s a good point that the indications and FDA approvals are slightly different, so it can be more challenging to get access unless you don’t have that PET imaging, which, by the insurer, could shift your stage, even if not in your clinical practice. That’s interesting and important.

I should emphasize that none of these drugs have been assessed head-to-head, so we’re looking at AEs for each of these drugs as compared with ADT [androgen deprivation therapy] plus placebo, but we’re not able to cross-compare across the trials. We’re not advocating that anyone do that, but just trying to speak from our experience. We’re not comparing across trials, except the agent vs placebo, all with ADT. Scott, what are your thoughts on the same question thinking about the differences, at least as compared with placebo, for these agents, their tolerability, and even their drug-drug interaction profiles?

Scott T. Tagawa, MD, MS, FACP: To me, that’s the clearest. The twice-a-day dosing for darolutamide with less drug-drug interactions is a nice trade-off for me. For patients who are on multiple drugs in whom I’m worried about interactions, that’s the one I will use most confidently in terms of fewer drug-drug interactions. I agree with you that we don’t have any head-to-head comparisons in the nonmetastatic setting, but we do now have a comparison to this metastatic CRPC setting, which is just in abstract form. We don’t have the cognitive data yet, but there was no major difference between enzalutamide and darolutamide in terms of the AE rates and patient preferences for darolutamide. That’s preliminary. There are some cognitive data coming from that trial as well as multiple other trials, including one that you’re leading. I’m interested to see some head-to-head data within a randomized trial.

The other interesting part about the French trial was the crossover design. Each individual patient was their own control in terms of preference and exposure for both. Maybe there’s a little less fatigue and a little more preference for darolutamide, but in that setting, nothing major. Twice a day vs once a day is something that’s different. There are slightly fewer drug-drug interactions. I go back to the noncastrate setting. Two vs 1 is better, so the early addition of any of these for this nonmetastatic, particularly short doubling time castration-resistant setting, is important.

Alicia K. Morgans, MD, MPH: I’d agree. That trial was interesting. Like you said, fatigue may have been a little different, but at the end of the day, these patients are often relatively asymptomatic, except for the symptoms that we’re giving them because of their ADT. Whatever we can do to keep them feeling as well as they can and not add onto that burden is going to be important. If they’re in agreement, we need to try to do whatever we can to get better disease control. From my perspective, that’s why it’s important to intensify when we can for the survival advantage. Your thoughts have all been interesting. Thank you all for your time and your expertise.

Transcript Edited for Clarity