Next-Generation Androgen Receptor Inhibitors in nmCRPC


A prostate cancer expert reviews trial design and efficacy data with next-generation androgen receptor inhibitors.

Audrey Sternberg: Can you briefly talk about next-generation androgen receptor inhibitors and how they differ from each other?

Aaron Berger, MD: Sure. The 3 medications—enzalutamide, apalutamide, and darolutamide—are very similar in terms of their mechanism of action, in terms of blocking the androgen receptor and the translocation to the nucleus, and then inhibiting transcription. Mechanistically, they all work very similarly. The molecules are slightly different sizes, which can account for a bit of the difference we see in some of the adverse effects.

Darolutamide typically has a little less of the central nervous system effects, such as fatigue, or potentially some lightheadedness, dizziness, and things that we sometimes may see. But mechanistically, they work very similarly. The designs of the 3 studies—ARAMIS, PROSPER, and SPARTAN—are very similar. The results of the studies are very similar as far as metastasis-free survival and overall survival. They’re all great drugs. It’s nice to have 3 good options that we didn’t have as recently as 4 or 5 years ago. The options right now for this disease state are much better than they were 5 or 6 years ago for patients.

In terms of deciding which one to use, it’s somewhat physician preference, if you have better experience with one over another. Sometimes there’s a reason why you might not use one vs the other. For example, if a patient has significant fatigue or any other more central nervous system issues, like gait abnormalities or difficulty walking, darolutamide may potentially be a better choice than enzalutamide or apalutamide. But in my experience, they’re all tolerated pretty well. They have a few different potential adverse effects that you need to be aware of with all of them. But in general, it’s nice to have multiple options that all work very well to not only improve metastasis-free survival for these patients, but also overall survival.

Audrey Sternberg: You touched on this a little bit, but can you review the SPARTAN, PROSPER, and ARAMIS trials as far as study design, patient populations, and key efficacy outcomes?

Aaron Berger, MD: Sure. All 3 trials had very similar patient populations with PSA [prostate-specific antigen] doubling times of 10 months or less. All the patients had rising PSA that was confirmed on more than 1 occasion, and castrate levels of testosterone, with testosterone levels less than 50 ng/dL. They were all looking at metastasis-free survival as the primary end point, and they all met statistical significance, showing improved benefit as far as metastasis-free survival vs placebo.

In the subsequent analyses of all of these studies, they’ve also found that all 3 medications offer benefits in terms of overall survival, especially with the enzalutamide and apalutamide trials. When they initially were published, the data weren’t mature enough to make a determination on overall survival. But in subsequent analyses, this is now borne out that they all have improvements in overall survival and metastasis-free survival.

In terms of study design, it was all 2:1 randomization, different types of patients in terms of their grade of prostate cancer, ages were similar, and the baseline demographics between the 3 studies were all pretty similar. I’d have to get into the weeds a bit as far all the baseline characteristics to find a lot of differences. But in general, the study design and outcomes were pretty similar.

This transcript has been edited for clarity.

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