LAUSR

0123456789();: Nature reviews | Urology Combination therapy with the androgen receptor (ar) inhibitor darolutamide in combination with docetaxel and androgen deprivation therapy (aDt) improves survival in men with metastatic hormone-sensitive prostate cancer (mHsPC) according to data from the recently published araseNs trial. Previous randomized phase iii trials have shown the clinical benefit of adding other ar-pathway inhibitors — abiraterone, enzalutamide or apalutamide — to aDt in men with hormone-sensitive disease. However, studies investigating addition of these ar-pathway inhibitors to aDt and docetaxel are more conflicting, with the PeaCe-1 trial of abiraterone showing benefit but the eNZaMet study of enzalutamide showing no survival benefit. the phase III ARAMIS trial showed the benefit of adding darolu tamide, a structurally distinct ar inhibitor with low penetrance of the blood–brain barrier to aDt in patients with non-metastatic castration-resistant prostate cancer (nmCrPC). these results led to the international phase iii araseNs trial of darolutamide in men with mHsPC. araseNs included 1,306 patients from 286 centres in 23 countries, who were randomly assigned 1:1 to receive darolutamide 600 mg or placebo twice daily in combination with aDt and docetaxel. all the patients received aDt with a luteinizing-hormone-releasing hormone (LHrH) agonist or an LHrH antagonist or underwent orchiectomy within 12 weeks before randomization and received six cycles of docetaxel (75 mg per m of body surface area on day 1 and every 21 days within 6 weeks after randomization). The primary end point was overall survival (Os) and secondary end points including time to CrPC, time to pain progression and symptomatic skeletal-event-free survival were also assessed. Primary OS analysis indicated that the risk of death was 32.5% lower in the darolutamide group than in the placebo group (Hr 0.68; 95% Ci 0.57–0.80; P < 0.001). Os at 4 years was 62.7% (95% Ci 58.7–66.7) in the darolutamide group and 50.4% (95% Ci 46.3–54.6) in the placebo group. this outcome was significant even though a large percentage of the placebo group went on to receive life-prolonging therapy. Furthermore, darolutamide was associated with significantly longer time to development of CrPC, time to pain progression, symptomatic skeletal-event-free survival and time to initiation of subsequent systemic therapy compared with placebo. incidence of adverse events was similar in both groups. Overall, these data support the use of darolutamide combined with aDt and docetaxel in men with mHsPC.