Final ARAMIS Data Confirm Darolutamide Efficacy Benefit in nmCRPC

A higher percentage of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) were alive at 3 years on treatment with darolutamide (Nubeqa) compared with placebo, according to published results from the final analysis of the phase 3 ARAMIS clinical trial.

Based on earlier metastasis-free survival (MFS) findings from ARAMIS, darolutamide was granted FDA approval as treatment of nmCRPC in July 2019. The MFS previously observed with darolutamide was 40.4 months compared with 18.4 months among patients given the placebo control. In the final analysis, overall survival (OS) data were mature, and the secondary and exploratory analysis results were reported.

ARAMIS is a randomized, double-blind included 1509 patients in the intention-to-treat population 955 of whom were enrolled in the darolutamide arm and 554 in the placebo arm. After 254 deaths in the study, 148 in the darolutamide arm and 106 in the placebo arm, 83% (95% CI, 80%-86%) of patients in the darolutamide arm were still alive at 3 years compared with only 77% (95% CI, 72%-81%) of the placebo arm. This resulted in a 31% lower risk of death with darolutamide treatment compared with placebo (HR, 0.69; 95% CI, 0.53-0.88; P =.003), a result that investigators led by Karim Fizazi, MD, considered to be significant.

Most deaths in the study were prostate cancer-related, including 80 out of 149 cases in the darolutamide arm and 56 out of 106 in the control arm. Notably, most deaths occurred after treatment discontinuation.

The Kaplan-Meier estimate of OS predicts a darolutamide benefit over placebo of HR 0.69 (95% CI, 0.53-0.88; P =.003).

Data on secondary and exploratory end points were also reported in the final analysis. The data showed that patients who received darolutamide had a time to pain progression of 53 months (95% CI, 47-60) compared with 32 months (95% CI, 22-43) in the placebo arm (HR, 0.65; 95% CI, 0.53-0.79; P <.001). The time to first use of cytotoxic chemotherapy was 83 months (95% CI, 80-86) in the darolutamide arm compared with 75 months (69-80) in the placebo arm (HR, 0.58; 95% CI, 0.44-0.76; P <.001). For the remaining secondary end point, time to first symptomatic skeletal event, the result was 96 months (95% CI, 95-98) in the darolutamide arm versus 92 months (89-96) in the placebo arm (HR, 0.48; 95% CI, 0.29-0.82; P =.005).

In terms of the 2 exploratory study end points, the time to first prostate cancer-related invasive procedure was 94 months (95% CI, 92-96) among patients who received darolutamide compared with 87 months (95% CI, 83-90) among those in the placebo group (HR, 0.42; 95% CI, 0.28-0.62). The time to initiation of subsequent antineoplastic therapy was 88 months (95% CI, 85-91) in the darolutamide group versus 70 months (95% CI, 64-76) in the placebo group (HR, 0.36; 95% CI, 0.27-0.48).

The safety analysis showed adverse events (AEs) in 85.7% of patients in the darolutamide arm and 79.2% of patients in the placebo arm. Overall, safety results from the final analysis were consistent with the primary analysis. The most common any-grade AEs in the darolutamide arm versus the placebo arm were fatigue (13.2% vs. 8.3%), bone fracture (5.5% vs. 3.6%), fall (5.2% vs. 4.9%), weight decrease (4.2% vs. 2.5%), and asthenic condition (4.0% vs. 3.1%), respectively. The most common grade 3/4 AE observed in the both treatment arms was hypertension, which occurred in only 3.5% of patients in the darolutamide arm and 2.3% in the placebo arm.

Regarding the safety analysis, Fizazi et al wrote, “After a median follow-up of 29.0 months in the overall trial population, darolutamide continued to have a favorable safety profile, similar to that described previously.”

“This updated analysis of the ARAMIS trial confirms the low potential for central nervous system-related effects expected with darolutamide, which has been postulated to be due to the very low penetration of the blood–brain barrier that has been reported in preclinical and clinical studies of darolutamide,” Fizazi et al concluded.

_Reference:

_{Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-9. doi: 10.1056/NEJMoa2001342}