Background: Enzalutamide (ENZA) is a highly effective treatment for patients (pts) with metastatic prostate cancer, but central nervous system (CNS)-associated side effects occur frequently and may hamper the quality of life. These side effects are addressed with dose reductions, while they potentially can be prevented by starting at a reduced dose, since androgen receptor saturation is already observed at dose levels above 60 mg once daily (OD) and ENZA plasma concentrations > 5 mg/L. We hypothesized that a lower starting dose of ENZA can reduce the risk of CNS side effects in frail pts while preserving efficacy. In this study (NCT03927391) the effect of a reduced dose of ENZA on fatigue and cognitive side effects is determined. Methods: This randomized multi-center trial compared the ENZA standard dose of 160 mg OD to the reduced dose of 120 mg OD in frail prostate cancer pts. At baseline, and 6, 12, and 24 weeks after start of ENZA, fatigue and cognitive side effects were measured by the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) questionnaires. A change in scores of 3.0 for the FACIT-F and 7.0 for the FACT-Cog was considered clinically relevant. Linear mixed effects models were used to study within and between-group differences in fatigue and cognitive side effects over time. Furthermore, ENZA plasma concentrations were measured after 6, 12, and 24 weeks of treatment and PSA response (>50% PSA decline) was compared between the two dosing regimens. Results: A total of 51 pts were included (25 reduced dose, 26 standard dose). Completion rates for the questionnaires were high throughout the study (>90%). Pts treated at the reduced dose showed no significant changes in FACIT-F and FACT-Cog scores over time. Pts treated at the standard dose showed increasingly worse FACIT-F and FACT-Cog scores. This resulted in clinically relevant and statistically significant better FACIT-F and FACT-Cog scores for pts treated at the reduced dose compared to pts treated at the standard dose after 24 weeks (table). All pts had therapeutic ENZA concentrations (>5 mg/L) throughout the study. PSA response did not differ between both groups (87% for 120mg OD vs 80% for 160mg OD, p=0.796). Conclusions: By starting with a reduced dose of ENZA of 120mg OD CNS side effects can be prevented, which might beneficially affect the quality of life of frail prostate cancer pts, without any indication of interference with efficacy endpoints. Clinical trial information: NCT03927391.

Higher scores represent less fatigue and cognitive side effects. * Significant p<0.05.