Treatment options for patients with metastatic, hormone-sensitive prostate cancer (mHSPC) are rapidly changing. The standard of care systemic therapy for these patients includes androgen deprivation therapy (ADT) in combination with either docetaxel chemotherapy or one of the androgen-receptor pathway targeted therapies (abiraterone, enzalutamide, apalutamide). This approach is based on survival benefit observed in several phase III clinical trials. More recently, the three-drug combination of ADT, docetaxel and abiraterone demonstrated further prolongation of survival (PEACE-1 trial). Interestingly, according to prespecified subgroup analysis from the ENZAMET trial, no survival gain was observed with enzalutamide plus ADT and concurrent docetaxel. At this year’s ASCO Genitourinary Cancer Symposium, results from the large, randomized, phase III ARASENS trial that compared survival among patients who received ADT plus docetaxel, with or without the potent androgen receptor inhibitor darolutamide, were presented. These data were published simultaneously in the New England Journal of Medicine.

In total, 1306 patients were randomized to receive either darolutamide or placebo in combination with ADT and docetaxel. At the time of primary analysis, the median follow-up was over 40 months for both groups. Compared with docetaxel plus ADT, the addition of darolutamide to docetaxel and ADT reduced the risk of death by 32.5% (hazard ratio [HR] 0.68; P < 0.001). The median treatment duration was 41.0 months with darolutamide vs 16.7 months with placebo. The median OS was not reached in the darolutamide group and was 48.9 months in the placebo group. At 4 years, OS in the darolutamide group was 62.7% compared with 50.4% in the placebo group. The survival benefit of darolutamide was consistent across most subgroups. Of note, significant OS benefit was observed despite more than 75% of patients in the placebo group receiving one or more subsequent systemic anticancer therapies (primarily different androgen-receptor inhibitors). In addition to the survival improvement, the darolutamide combination significantly improved secondary endpoints, including time to development of castration-resistant disease, time to pain progression, symptomatic skeletal event-free survival (as well as the time to a first symptomatic skeletal event). The time to initiation of subsequent systemic anti-cancer therapy was also significantly longer. Importantly, the frequency of adverse events (AEs) of any grade were similar between the two groups, including grade 3 – 5 AEs and serious AEs. Neutropenia was the most common grade 3 or grade 4 AE (33.7% of the darolutamide group and 34.2% of the placebo group). Adverse events of special interest in prostate cancer patients treated with androgen receptor pathway inhibitors, such as fatigue, falls, fractures, mental impairment, and cardiovascular events were similar between study arms. 

The authors concluded that the results of the trial support the use of darolutamide in combination with ADT and docetaxel in patients with mHSPC, and are consistent with those of the PEACE-1 trial.  In assessing the trial’s strengths and weaknesses, they noted that the large sample size enabled a strong statistical analysis. However, since all patients included in the trial had ECOG PS 0 – 1, the effects of the darolutamide regimen on patients with a poor performance status cannot be predicted. In addition, as most ARASENS participants had bone metastases, visceral metastases, or both at diagnosis, the trial does not provide benefit-risk guidance for patients with mHSPC and better prognoses, such as those with recurrent metastatic disease or with node-metastases only.

Reference:
Smith MR, et al. New Engl J Med. 2022;386:1132-42.