AR Inhibitor Selection in Nonmetastatic Castration-Resistant Prostate Cancer

Shared insight on the selection of specific androgen receptor inhibitors for patients with nonmetastatic castration-resistant prostate cancer.


Robert Dreicer, MD, MS, MACP, FASCO: Dr George, I want you to briefly comment. We’ve got the 3 large randomized trials, and again, these are not new data, so I don’t want to spend a whole lot of time. What I’d like to hear from you is about this patient, in an environment where PSMA PET [prostate-specific membrane antigen positron emission tomography] is not going to be done, for whatever reason. You’ve got this guy, is this the patient for whom you’re going to use a next-generation ARI [androgen receptor inhibitor]? How do you briefly explain the risk and benefit? We all know that the data are compelling, they all showed overall survival, the hazard ratios were similar and meaningful. How do you make treatment decisions based on the data? How do you present the information to a patient and then make a clinical judgment about which drug to recommend?

Saby George, MD, FACP: Technically this is a patient with nonmetastatic castration-resistant prostate cancer. The patient doesn’t have any symptoms. All we see are the 2 small lymph nodes. Three studies— of darolutamide, apalutamide, and enzalutamide—demonstrated that the application of these agents early can prolong metastasis-free survival, meaning that the time to metastasis can be pushed to roughly 40 months compared to 16 months by not using them. That’s a significant improvement in metastasis-free survival. Metastasis-free survival was defined based on traditional imaging. That’s the bone scan and regular CT scans. While we do have availability of these newer modalities of imaging using PSMA, etc, they may have a higher sensitivity and specificity, but technically, it’s still the same patient, whether you do the scan or not. It’s the same space that we’re talking about. Just because we are able to detect this micrometastatic or low-burden disease using a newer modality of scan, that doesn’t mean that we should not deny them the treatment. It has been shown, as I mentioned, in 3 large studies that the newer AR [androgen receptor] blocking agents like darolutamide, apalutamide, and enzalutamide have the ability to prolong metastasis-free survival and SSE, time to symptomatic skeletal events, and improve quality of life also. It’s important to apply the data in this space.

Robert Dreicer, MD, MS, MACP, FASCO: Tell me again, you’ve got the 3 drugs, the data are the same, when you make a recommendation, what is your routine recommendation, and what’s the rationale for it?

Saby George, MD, FACP: I have the most experience with enzalutamide, since 2012 or 2013 onward, so that tends to be my default drug, and it’s been around a long time. Then, apalutamide came through, and darolutamide came afterward. The difference is that as you know, there has been a slight increase in the incidence of reported seizure disorders with the use of enzalutamide…does have a low frequency of that. Safety-wise and also adverse event-wise, darolutamide may have a better edge over the other two. That’s been my experience even though I don’t have high volumes of patients in this space. With limited experience, I think darolutamide is safer, with a similar efficacy, so safety is most important, especially because most of these patients are in their 60s, 70s, and 80s, so we have to be careful when we choose a drug for these patients.

Robert Dreicer, MD, MS, MACP, FASCO: Dr Scholz, let me get your thoughts on choice of drug in this setting.

Mark Scholz, MD: Of course, we were thrilled when enzalutamide and abiraterone came out, it changed my day-to-day practice. There was a drastic reduction in the use of chemotherapy because people go into extended remissions. To answer your question, the problem with enzalutamide for me has been unexplained exacerbation of fatigue. That can be quite debilitating in 20%, 25% of patients. I’m trying to maintain a positive outlook for my patients. When I give them pills that can really make them tired…I have shifted over to using darolutamide because that same unexplained fatigue problem seems to be far less frequent. There is a general fatigue that occurs with all testosterone deprivation, but I’m talking about an additional layer of severe fatigue that occurs in a minority of patients on enzalutamide.

Transcript edited for clarity.

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