Adjuvant darolutamide prolongs survival in metastatic, hormone-sensitive prostate cancer

Researchers from a phase 3 clinical trial report that addition of the androgen-receptor inhibitor darolutamide to androgen-deprivation therapy and chemotherapy significantly prolongs the survival of men with metastatic, hormone-sensitive prostate cancer.

The findings appeared on February 18, 2022 in the NEJM/New England Journal of Medicine.

As background, the authors noted that darolutamide therapy has previously been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. But, prior to this trial, the efficacy of combination of darolutamide, androgen-deprivation therapy and docetaxel for survival among patients with metastatic, hormone-sensitive prostate cancer was unknown.

The investigators enrolled and randomized 1,306 subjects, 651 to the darolutamide group and 655 to the placebo group; 86.1% of the patients had metastatic disease at diagnosis.

Darolutamide-treated subjects received a dose of 600 mg (two 300-mg tablets) twice daily. Placebo-treated subjects received matching placebo pills. Both cohorts also received combination therapy with androgen-deprivation therapy and docetaxel.

The primary end point was overall survival.

The investigators compared survival rates after 533 subjects had died, after a median follow-up of approximately 3.5 years.

They reported that darolutamide-treated subjects achieved a 32.5% lower risk of death than placebo-treated subjects. (P<0.001)

Darolutamide-treated subjects also achieved greater delays in development of castration-resistant prostate cancer, pain, and the need for other anti-cancer therapies.

Adverse events were similar in the two groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide-treated group and 63.5% in the placebo-treated group. The most common adverse event was grade 3 or 4 neutropenia, 33.7% in the darolutamide-treated group and 34.2% in the placebo-treated group.

The authors concluded, “In this international, randomized, double-blind, placebo-controlled, phase 3 trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer among patients who received darolutamide plus androgen-deprivation therapy and docetaxel than among those who received androgen-deprivation therapy and docetaxel alone. This survival benefit was observed despite a high percentage of patients who received subsequent life-prolonging systemic therapy in the placebo group. The survival benefit of darolutamide was consistent across most subgroups. The time to the development of castration-resistant disease was significantly longer in the patients who received darolutamide, and improvements were observed with respect to the other key secondary end points. The incidence, severity, and nature of adverse events were consistent with the established safety profiles of androgen-deprivation therapy and docetaxel.”