Background <p>Enzalutamide at standard doses (160 mg/day) is effective in advanced prostate cancer (PCa) but is associated with considerable adverse events (AEs) and high financial costs. Preliminary reports suggest that low/intermediate doses (≤80 mg/day) retain efficacy while reducing toxicity. This study evaluates the efficacy and safety of low/intermediate dose vs standard-dose enzalutamide in a real-world cohort.</p> Methods <p>This retrospective observational study included 140 assessable patients treated with enzalutamide for metastatic castration resistant (80%) or sensitive (20%) PCa. Patients were categorized by cumulative average daily dose relative to the standard dose (160 mg/day): low (≤50%, n = 11), intermediate (&gt;50% and ≤80%, n = 16), and high (&gt;80%, n = 113). The primary endpoint was the 12-month progression-free survival (PFS) by restricted mean time. Secondary endpoints included PSA response (decline ≥50% at 3 months), overall survival (OS) at 36 months and worsening of AEs of interest (fatigue, neurological disorders, hypertension).</p> Results <p>There were no significant differences in PFS at 12 months on high vs intermediate dose (10.4 vs 11.4 mo, <i>p</i>= 0.09) and high vs low dose (10.4 vs 9.2 mo, <i>p </i>= 0.37), nor was there on PSA response (70% vs 75% vs 60% on high, intermediate, low doses, respectively). Intermediate or low doses showed no evidence of adverse effects on OS at 36 months. The rate of fatigue worsening on high vs intermediate vs low dose was 61.1%, 63.0% and 27.3% (<i>p </i>= 0.03 for high vs low).</p> Conclusions <p>Low/intermediate doses of enzalutamide show comparable efficacy than high dose while improving tolerability, indicating the need for further search of its optimal dose. Moreover, our findings prompt a study of the optimal dose in advanced disease and in the prevention/interception setting in patients with low/intermediate risk PCa under active surveillance.</p>