Metastatic Castrate-Resistant Prostate Cancer: Androgen Receptor Inhibitors


Dr. Karim Fizazi describes the use of next generation androgen receptor inhibitors in treatment of metastatic castrate-resistant prostate cancer.

Karim Fizazi, MD, PhD: Among what I call the second generation of androgen receptor axis inhibitors, I would clearly list abiraterone, enzalutamide, apalutamide, and darolutamide. Abiraterone is actually an androgen biosynthesis inhibitor, and its metabolism targets the androgen receptor directly. There are 3 drugs directly targeting the androgen receptor: enzalutamide, apalutamide, and darolutamide.

Two of them are chemically very similar; enzalutamide and apalutamide were both invented by the same team and developed by 2 different companies. The chemical structure is very similar and their results from both an efficacy standpoint and a safety standpoint are very similar. For example, we see some fatigue associated probably with the fact that these agents penetrate the blood-brain barrier, some excess in falls and fractures.

The third agent in this family, darolutamide, was invented by a different company in Finland. Its chemical structure makes a curve, which helps the drug not penetrate the blood-brain barrier. Thanks to this property, the drug seems to be better tolerated, at least when we’re comparing each of these drugs with its own placebo in large phase 3 trials. We don’t see much safety difference for darolutamide when compared to its placebo, while we do see some different with the other agents.

We need to remember that many patients with advanced prostate cancer are older than 70, and they might already suffer from cognitive impairment. Of course, this is not always the case, and cognitive impairments can also happen earlier during life. When I started using enzalutamide at full dose in the elderly, many patients complained about having difficulty concentrating or memorizing things, or if it were not the patient, the wife would tell me. Sometimes it was a difficult consultation because the wife was getting either upset or at least scared about what was ongoing, and we realized that in these men, we should probably not use full dose enzalutamide if we want to prevent those adverse effects. When I’m using this agent in the elderly, I tend to use it at half of the dose.

In my experience with darolutamide, we don’t see this happening. This is supported by data from randomized trials when comparing darolutamide with a placebo, we couldn’t see an excess of cognitive impairments or falls and fractures, compared to the placebo.

Transcript edited for clarity.

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