In an international, randomised, double-blind, placebo-controlled, phase III ARASENS study that involved patients with metastatic, hormone-sensitive prostate cancer, overall survival (OS) was significantly longer among patients who received darolutamide plus androgen-deprivation therapy (ADT) and docetaxel than among those who received placebo plus ADT and docetaxel. The OS 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 endpoints. The results were presented by Dr. Matthew Raymond Smith of the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, MA, US at 2022 ASCO Genitourinary Cancers Symposium (17-19 February 2022, San Francisco, CA, US & Online) and simultaneously published on behalf of the ARASENS investigators in The New England Journal of Medicine.
Darolutamide is a potent androgen receptor inhibitor that has been associated with increased OS among patients with non-metastatic, castration-resistant prostate cancer. Studies involving patients with prostate cancer, including the phase III ARAMIS study that involved patients with non-metastatic, castration-resistant prostate cancer, have shown that darolutamide has potent antitumour efficacy. In the ARAMIS study, the median metastasis-free survival was almost 2 years longer and the risk of death was 31% lower among patients who received darolutamide with ADT than among those who received placebo with ADT, and the incidence of adverse events was similar in the two groups.
In the phase III ARASENS study, the study team evaluated the efficacy and safety of darolutamide added to ADT and docetaxel in patients with metastatic, hormone-sensitive prostate cancer. The investigators randomly assigned patients in a 1:1 ratio to receive darolutamide or matching placebo, both in combination with ADT and docetaxel. The primary endpoint was OS.
The primary analysis involved 1306 patients, of whom 651 in the darolutamide group and 655 in the placebo group. At the time of the initial diagnosis, 86.1% of the patients had metastatic disease. At the data cut-off date for the primary analysis (25 October 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval 0.57-0.80; p < 0.001).
Darolutamide was also associated with consistent benefits with respect to the secondary endpoints and prespecified subgroups.
Adverse events were similar in the two groups, and the incidences of the most common adverse events occurring in ≥10% of the patients were highest during the docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group. Neutropenia was the most common grade 3 or 4 adverse event in 33.7% and 34.2%, respectively.
The authors commented that most patients who were enrolled in the study had metastatic disease, with bone metastases, visceral metastases, or both, at the time of the initial diagnosis. Thus, limited information is available on the benefit–risk considerations for patients with metastatic, hormone-sensitive prostate cancer and a better prognosis, including those with recurrent metastatic disease, node-only metastases, or both. In addition, the efficacy and safety of combination therapy are unknown in patients with a poor performance status, because the study included only patients with an ECOG performance status 0 or 1.
The authors concluded that in this study that involved patients with metastatic, hormone-sensitive prostate cancer, OS was significantly longer with the combination of darolutamide plus ADT and docetaxel than with placebo plus ADT and docetaxel. The addition of darolutamide led to improvement in key secondary endpoints. The frequency of adverse events was similar in the two groups. The study results support the use of darolutamide in combination with ADT and docetaxel in patients with metastatic, hormone-sensitive prostate cancer.
The study was funded by Bayer and Orion Pharma.
References
Smith MR, Hussain M, Saad F, et al. for the ARASENS Trial Investigators. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med; Published online 17 February 2022. DOI: 10.1056/NEJMoa2119115
Smith MR, Hussain M, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. J Clin Oncol 2022;40:(suppl 6; abstr 13). DOI: 10.1200/JCO.2022.40.6_suppl.013