Darolutamide, a potent androgen-receptor inhibitor, is associated with increased overall survival in non-metastatic, castration-resistant prostate cancer patients. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival in patients with metastatic, hormone-sensitive prostate cancer was, until now, unknown. Results of the phase III ARASENS trial show that the addition of darolutamide improves overall survival, without an increase in adverse events.
Standard treatment for patients with metastatic, hormone-sensitive prostate cancer (HSPC) includes the addition of either docetaxel or an androgen-receptor pathway inhibitor to androgen-deprivation therapy (ADT). Several phase III trials have shown that the addition of an androgen-receptor pathway inhibitor (abiraterone, enzalutamide, or apalutamide) to ADT has greater clinical benefit than ADT alone. However, combination therapy with an androgen-receptor pathway inhibitor, ADT, and docetaxel have shown conflicting results. Darolutamide is a structurally distinct androgen-receptor inhibitor that has been associated with increased overall survival among patients with non-metastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, ADT, and docetaxel would increase survival among patients with metastatic, HSPC is unknown and was assessed in the phase III ARASENS trial.
The randomised, double-blind, phase III ARASENS trial enrolled adult patients with histologically or cytologically confirmed prostate cancer and metastases detected on bone scanning, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Eligible patients had to be candidates for androgen-deprivation therapy and docetaxel. Patients were randomly assigned in a 1:1 ratio to receive either darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily with food) or matched placebo, both in combination with ADT and docetaxel. The primary endpoint was overall survival.
Between November 2016 and June 2018, a total of 1,306 patients were randomised. Of them, 1,305 patients (651 in the darolutamide group and 654 in the placebo group) were included in the full analysis set, and 1,302 patients (652 in the darolutamide group and 650 in the placebo group) were included in the safety analysis set. Demographic and baseline characteristics were well balanced in the two groups. At the data cut-off date for the primary analysis, the median treatment duration was longer in the darolutamide group (41.0 months) than in the placebo group (16.7 months), and a higher percentage of patients in the darolutamide group (45.9%) than in the placebo group (19.1%) were still receiving the assigned trial treatment.
The primary analysis of overall survival was performed after 533 patients had died. The risk of death was 32.5% lower in the darolutamide group than in the placebo group (HR[95%CI]: 0.68[0.57-0.80]; p< 0.001). The overall survival at four years was 62.7% in the darolutamide group and 50.4% in the placebo group. Furthermore, darolutamide was associated with significantly greater benefits than placebo for the first five hierarchically tested secondary efficacy endpoints. The time to development of castration-resistant disease was significantly longer in the darolutamide group (HR[95%CI]: 0.36[0.30-0.42]; p< 0.001). The time to pain progression was also significantly longer in the darolutamide group (HR[95%CI]: 0.79[0.66-0.95]; p= 0.01), as were symptomatic skeletal event–free survival (HR[95%CI]: 0.61[0.52-0.72]; p< 0.001) and the time to a first symptomatic skeletal event (HR[95%CI]: 0.71[0.54-0.94]; p= 0.02). Additionally, the time to the initiation of subsequent systemic antineoplastic therapy was significantly longer with darolutamide (HR[95%CI]: 0.39[0.33-0.46]; p< 0.001).
The incidence of adverse events (AEs) of any grade, grade 3 to 5 adverse events, and serious adverse events was similar in the two groups. The incidence of the most common AEs (occurring in ≥10% of the patients) was the highest in both groups during the period when patients received both docetaxel and either darolutamide or placebo, and progressively decreased thereafter. The frequency of grade 3 or 4 AEs was 66.1% in the darolutamide group and 63.5% in the placebo group. The most common grade 3 or 4 AE was neutropenia (33.7% and 34.2%, respectively).
The results of the phase III ARASENS trial support the use of darolutamide in combination with androgen-deprivation therapy and docetaxel in patients with metastatic HSPC. This combination resulted in increased overall survival and improved the key secondary endpoints, including time to development of castration-resistant disease, time to pain progression, symptomatic skeletal event–free survival, time to a first symptomatic skeletal event, and initiation of subsequent systemic antineoplastic therapy. The frequency of adverse events was similar in the two groups.
Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-42.