The phase III ARAMIS study shows that the androgen-receptor antagonist darolutamide delays metastasis in men with castration-resistant prostate cancer by a median of 22 months compared with a placebo. Researchers also found that side effects associated with other drugs in this class were no more common in the placebo group than the darolutamide group.

The next-generation androgen-receptor inhibitor darolutamide (Bayer/Orion) extends metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer and may be safer than two similar drugs recently approved for the same patient population. That's according to data from the ARAMIS trial presented at the 2019 Genitourinary Cancers Symposium in San Francisco, CA, and concurrently published in The New England Journal of Medicine.

The androgen-receptor inhibitors apalutamide (Erleada; Janssen Oncology) and enzalutamide (Xtandi; Astellas/Pfizer) received FDA approval in 2018. The apalutamide decision was based on data from the SPARTAN trial, which found that the drug increased metastasis-free survival by 24.3 months over a placebo. The PROSPER trial showed similar results for enzalutamide, which provided a metastasis-free survival benefit of 21.9 months over a placebo. However, both drugs are associated with adverse events such as falls and seizures. Because darolutamide has a distinct structure and doesn't cross the blood–brain barrier as readily as apalutamide and enzalutamide, researchers hypothesized that it might be better tolerated.

In the phase III ARAMIS trial, Karim Fizazi, MD, of the Institut Gustave Roussy in Villejuif, France, and colleagues randomly assigned 1,509 men with nonmetastatic, castration-resistant prostate cancer to receive either darolutamide or a placebo while continuing androgen-deprivation therapy.

After a median follow-up period of 17.9 months, median metastasis-free survival was 22 months longer in the darolutamide-treated patients than in the control group, suggesting that the drug is about as effective as apalutamide and enzalutamide. Darolutamide was also associated with improvements in all secondary endpoints, including overall survival and time to pain progression.

The rate of side effects of any grade was 83.2% in patients treated with darolutamide and 76.9% in those who received a placebo. Grade 3 or 4 adverse effects occurred in 24.7% of the darolutamide-treated patients and in 19.5% of the control patients. However, the darolutamide and placebo groups differed little in the incidence of side effects associated with other next-generation androgen-receptor inhibitors. For example, seizures occurred in 0.2% of patients in both groups. Falls were nearly equivalent—4.2% in the darolutamide group versus 4.7% in the placebo group.

“Darolutamide not only is very active in men with aggressive prostate cancer, but also it is very well tolerated in this population,” says Fizazi.

“It's a high-quality study,” says Rahul Aggarwal, MD, of the University of California, San Francisco. “There's an unambiguous positive result of darolutamide in patients with nonmetastatic castration-resistant prostate cancer, and it will likely lead to approval of the drug.” The drug was granted Fast Track status by the FDA, and based on the ARAMIS results, Bayer and co-developer Orion completed their application for approval at the end of February.

Darolutamide's lower toxicity does appear to distinguish it from the other two drugs, says Nancy Dawson, MD, of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. “On the surface, they've made a good argument that it's safer,” she says, but trials comparing all three drugs haven't been done.

Both physicians say they would prescribe the drug if it is approved—but whether they would choose it over apalutamide and enzalutamide would depend on a variety of factors, including cost and experience with the drugs. –Mitch Leslie