Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896 ), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

We recently published results from the final prespecified analysis of overall survival (OS) in the ARCHES trial, a phase III, double-blind study of enzalutamide (160 mg once daily) plus androgen deprivation therapy (ADT) versus placebo plus ADT. 1 In that analysis, enzalutamide plus ADT demonstrated a clinically meaningful and statistically significant increase in OS compared with placebo plus ADT (hazard ratio [HR], 0.66; 95% CI, 0.53 to 0.81; log-rank P , .001).Sun and Wei 2 have raised concerns about the use and interpretation of the HR for the OS end point and a lack of median Kaplan-Meier (KM) estimates from the data. They note that the validity of the HR depends on a proportional hazards assumption and suggest that this assumption is likely invalid. In our analysis, we considered the proportional hazards assumption to be appropriate, as observed by a visual examination of the log-log plot and the Kolmogorov-type supremum test (P 5 .4440). Furthermore, the HR is not the sole descriptor of treatment effect presented; we also presented the KM curve and provided KM estimates at 24, 36, and 48 months. 1 The HR is appropriate for these data and supported by the summaries of the KM curves and by the log-rank test; the KM curves and logrank test do not require proportional hazards assumptions and are independent of the Cox HR. These statistics are clinically meaningful to clinicians and well-understood by the scientific community.