BACKGROUND: In the ARCHES study in metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) versus ADT alone. OBJECTIVE: To evaluate patient-reported outcomes (PROs) to week 73. DESIGN, SETTING, AND PARTICIPANTS: ARCHES (NCT02677896) was a randomised, double-blind, placebo-controlled, phase 3 study in mHSPC patients. INTERVENTION: Enzalutamide (160 mg/day) plus ADT or placebo plus ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PROs were assessed at baseline, week 13, and every 12 wk until disease progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate 25 (QLQ-PR25), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory Short Form, and EuroQoL 5-Dimensions, 5-Levels (EQ-5D-5 L) instruments. Endpoints included time to first (TTFD) and first confirmed (TTFCD) clinically meaningful deterioration (using predefined questionnaire thresholds) in health-related quality of life (HRQoL) and pain. RESULTS AND LIMITATIONS: A total of 1150 patients received ADT plus enzalutamide (n = 574) or placebo (n = 576). Baseline PRO scores indicated high HRQoL and low pain, which was generally maintained in both groups. There were no statistically significant (nominal p > 0.05) between-group differences that occurred in both TTFD and TTFCD together for QLQ-PR25 and FACT-P scores. Enzalutamide significantly delayed TTFD in worst pain (by ∼3 mo; nominal p = 0.032), pain severity (nominal p = 0.021), and EQ-5D-5 L visual analogue scale score (nominal p = 0.0070) versus placebo (not significant for confirmed deterioration for pain outcomes). Enzalutamide delays deterioration in several HRQoL subscales and pain severity in high-volume disease. CONCLUSIONS: Enzalutamide plus ADT enables men with mHSPC to maintain high-functioning HRQoL and low symptom burden. PATIENT SUMMARY: This study examined the effect on health-related quality of life and pain of adding enzalutamide or placebo to androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer. Addition of enzalutamide allowed patients to maintain their health-related quality of life.