Background
Phase III, double-blind, placebo-controlled RCT. 1150 patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC, M1), including high-volume (63%) and low-volume (37%) disease and previously treated (prior docetaxel allowed, 18%) and docetaxel-naïve patients. Patients received ongoing ADT plus investigational or placebo.
Interventions and follow up
Arm A: Enzalutamide 160mg/day orally + ongoing ADT
Arm B: Placebo + ongoing ADT
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 14.4 mo (rPFS); 44.6 mo (OS update)
Arm B: Placebo + ongoing ADT
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 14.4 mo (rPFS); 44.6 mo (OS update)
Results
rPFS: Not reached vs 19.0 mo, HR 0.39, P<.001
OS: Not reached vs 64.3 mo, HR 0.66, P=.0008
Time to PSA progression: HR 0.19
PSA undetectable (<0.2 ng/mL): 67.9% vs 17.5%
OS: Not reached vs 64.3 mo, HR 0.66, P=.0008
Time to PSA progression: HR 0.19
PSA undetectable (<0.2 ng/mL): 67.9% vs 17.5%
Adverse events
Overall grade ≥3 AEs: 24.3% vs 25.6% (similar between arms)
Constitutional: Fatigue (any grade) 26.7% vs 16.9%; hot flush 12.5% vs 9.7%
Cardiovascular / neurologic: Hypertension grade ≥3 3.7% vs 2.5%; seizure 0.4% vs 0%
Treatment discontinuation due to AEs: 7.9% vs 9.1%
Constitutional: Fatigue (any grade) 26.7% vs 16.9%; hot flush 12.5% vs 9.7%
Cardiovascular / neurologic: Hypertension grade ≥3 3.7% vs 2.5%; seizure 0.4% vs 0%
Treatment discontinuation due to AEs: 7.9% vs 9.1%
Conclusions
Enzalutamide added to ADT significantly improved rPFS and OS in mHSPC, including in both high-volume and low-volume disease subgroups and in prior-docetaxel and docetaxel-naïve patients. These results established enzalutamide + ADT as a standard first-line option across mHSPC subgroups.
Key Limitations
Key Limitations: The rPFS primary endpoint was assessed by blinded central review at relatively short follow-up; OS matured in the update. Prior docetaxel was permitted in ~18% of patients — a more heterogeneous population than pure treatment-naïve mHSPC trials. Crossover from placebo to enzalutamide upon progression confounds OS. The absolute OS benefit magnitude requires contextualizing within the full mHSPC treatment landscape, which now includes triplet therapy options (PEACE-1, ARASENS) for high-volume/high-risk patients.
Clinical Context
ARCHES confirmed enzalutamide + ADT as a standard in mHSPC (FDA approved 2019), consistent with ENZAMET. The OS update solidified the benefit. Like ENZAMET, ARCHES allowed prior docetaxel, broadening its applicability. In high-volume de novo mHSPC in fit patients, triplet regimens (enzalutamide or abiraterone or darolutamide + docetaxel + ADT) have largely supplanted doublet ARPI + ADT as preferred intensified first-line therapy per current ESMO guidelines.
References