Background and Objective <p>Pain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug–drug interactions. Morphine is generally preferred because of its favorable metabolic profile, but the effect of enzalutamide on the pharmacokinetics of morphine is unclear. The objective of this study was to assess whether a drug–drug interaction exists between enzalutamide and morphine in patients with prostate cancer.</p> Methods <p>In a multicenter two-arm parallel study, 24 men with prostate cancer received morphine with enzalutamide (<i>n</i> = 12) and without enzalutamide (<i>n</i> = 12). Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide were measured. Pharmacokinetic parameters were calculated using a non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration–time curves were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR of morphine was within the range of 0.5–2.0.</p> Results <p>Morphine exposure was similar between both groups, with the 90% CI falling within the range of 0.5–2.0 (GMR 1.01; 90% CI 0.77–1.31). The exposure of morphine-6-glucuronide was increased with enzalutamide (GMR 1.77; 90% CI 1.43–2.17).</p> Conclusions <p>The exposure of morphine was unaffected by enzalutamide, while morphine-6-glucuronide exposure was increased. Because of the inconclusive potency of morphine-6-glucuronide and its uncertain ability to cross the blood–brain barrier, the increase is likely of modest clinical significance. Therefore, morphine and enzalutamide can be safely combined when starting at a low dose and titrated based on efficacy and tolerability.</p> Clinical Trial Registration <p>NCT05339672.</p>