Efficacy and toxicity of low-doses versus standard-dose enzalutamide in advanced prostate cancer: A real-world study with implications for cancer prevention/interception.

10527 Background: Prostate cancer (PCa) is the most frequent cancer in males in the US and EU. Enzalutamide is effective in biochemically recurrent and advanced PCa but is associated with considerable adverse events (AEs) at standard doses (160 mg/day). In the ENACT trial, enzalutamide monotherapy reduced the risk of PCa progression compared to active surveillance (AS) in patients with intermediate/low-risk, but AEs were frequent (eg, 55% fatigue). Preliminary case 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 advanced PCa in a real-world Italian cohort. Methods: This single-center, retrospective observational study included 140 assessable metastatic PCa patients treated with enzalutamide for castration resistant (80%) or sensitive (20%) PCa between August 1, 2014 and December 31, 2023. Patients were categorized based on the total dose (actual vs predicted) taken: low (L, ≤50%, n = 11), intermediate (I, > 50% and ≤80%, n = 16), and high (H, > 80%, n = 113). The primary endpoint was the 12 month progression-free survival (PFS) by restricted mean survival time to account for violation of proportional hazards assumption. Secondary endpoints included PSA response (decline ≥50% at 3 months), overall survival (OS) at 36 months and worsening of AEs of special interest (fatigue, neurological disorders, hypertension). PFS and OS were adjusted for ECOG performance status at baseline. Results: The three dose groups were not different at baseline on PSA, BMI, Gleason Score, age and castration resistance. The choice of L dose treatment at baseline was due to clinical judgment in 82% of cases (PS > 0 or age > 80), whereas the I dose was due to toxicity reduction after initial high dose in 63%. The median follow-up time was 13.6 months [IQR, 7.2 – 23.1]. There were no significant differences in PFS at 12 months on H vs I dose (10.4 vs 11.4 mo, p = 0.09) and H vs L dose (10.4 vs 9.2 mo, p = 0.37). There was no difference among dose groups in PSA response (70% vs 75% vs 60% on H, I, L, respectively). The use of I or L doses showed no evidence of adverse effects on OS at 36 months. The rate of fatigue worsening on H vs I vs L dose was 61.1%, 63.0% and 27.3% ( p = 0.03 for H vs L). Worsening of neurological disorders and hypertension was 19.5%, 18.8% and 0% and 18.6%, 18.8% and 9.1% on H vs I vs L, respectively. Conclusions: In our real-life observational cohort, low/intermediate doses of enzalutamide show comparable efficacy relative to high dose while improving tolerability, indicating the need for further search of the optimal dose of this expensive drug. Moreover, our findings prompt a study of low-intermediate dose enzalutamide in the prevention/interception setting in patients with low/intermediate risk prostate cancer under AS.