Non-metastatic CRPC: treatment selection

Alicia K. Morgans, MD, MPH: One of the things that is 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 somewhat more frequently than darolutamide, which has a slightly different structure from the other two. Sandy, in your experience, does that make a difference in your decision making? Do you think the AE [adverse effects] are different? What are your thoughts?

Sandy Srinivas, MD: At least in the patients in whom I have used it, darolutamide is better tolerated. There is no cognitive dysfunction. At least from a clinical trial perspective, there have been fewer fractures and falls. In real life, it is better tolerated than apalutamide or enzalutamide. Maybe this is where this imaging becomes a problem, because if you look at these drugs, enzalutamide is approved across the spectrum so it doesn’t matter if someone has a PET scan. [positron emission tomography] imaging that is positive if you are going to treat them with AR [androgen receptor]-targeted drug. But if you get down to the nitty-gritty of drug approval and third party payers, darolutamide is only approved in the non-metastatic setting. Like Scott, I also use this to see how he fits. If I use conventional imaging and it is negative, I recommend darolutamide for these patients.

Alicia K. Morgans, MD, MPH: It’s a good point that the indications and FDA approvals are slightly different, so it may be more difficult to access it unless you don’t have that PET scan, which the insurer might change. your stadium, even if it is not in your practice clinic. It is interesting and important.

I must point out that none of these drugs have been evaluated face to face, so we are looking at the ARs for each of these drugs versus ADT. [androgen deprivation therapy] plus a placebo, but we are unable to compare the trials. We are not advocating that anyone do this, but are just trying to talk about our experience. We do not compare between trials except agent versus placebo, all with ADT. Scott, how do you feel about the same question when you think about the differences, at least compared to placebo, for these agents, their tolerability and even their drug interaction profiles?

Scott T. Tagawa, MD, MS, FACP: For me, this is the clearest. The twice daily dosage of darolutamide with fewer drug interactions is a good compromise for me. For patients who take multiple drugs and in whom I am concerned about interactions, this is the one I will use with the most confidence in terms of reducing drug interactions. I agree with you that we don’t have direct comparisons in the non-metastatic setting, but now we have a comparison with this metastatic CRPC framework, which is just in abstract form. Cognitive data is not yet available, but there was no major difference between enzalutamide and darolutamide in terms of AE rates and patient preferences for darolutamide. It’s preliminary. There is cognitive data from this trial as well as several other trials, including one that you are leading. I am interested in seeing direct data from a randomized trial.

The other interesting part of the French essay was the cross design. Each patient was their own control in terms of preference and exposure for both. Perhaps there is a little less fatigue and a little more preference for darolutamide, but in this context, nothing too serious. Twice a day versus once a day is something different. There are a little less drug interactions. I come back to the non-castration parameter. Two to 1 is better, so adding one of these parameters early for this particularly short, non-metastatic castration resistance parameter is important.

Alicia K. Morgans, MD, MPH: I would agree. This trial was interesting. Like you said, the fatigue might have been a little different, but at the end of the day these patients are often relatively asymptomatic with the exception of the symptoms we give them due to their ADT. Anything we can do to make them feel as good as they can and not add to that burden will be important. If they agree, we must try to do everything in our power to better control the disease. From my perspective, that’s why it’s important to step up when we can for the benefit of survival. Your thoughts have all been interesting. Thank you all for your time and expertise.

Transcription edited for clarity

Martin E. Berry