Simple SummaryProstate cancer radiation therapy (RT) to the pelvis is one of the curative approaches for patients with localized prostate cancer. Most patients treated with prostate RT experience some degree of radiation-induced lower urinary tract symptoms (RI-LUTSs). These symptoms may have a negative impact on patients’ quality of life after treatment. The aim of our prospective study was to determine if prophylactic α-blockers improved RI-LUTSs in men undergoing prostate RT. Overall, we found that there were no important effects of prophylactic α-blockers on RI-LUTSs. Therefore, treating prostate cancer patients preventatively with α-blockers may cause additional drug toxicity and financial burden without significantly improving their urinary symptoms. This trial was registered with ClinicalTrials.gov under the registration number NCT02220829.AbstractPurpose: The present phase III randomized trial assessed the efficacy of prophylactic versus therapeutic α-blockers at improving RI-LUTSs in prostate cancer patients receiving external beam radiotherapy (EBRT). Methods: A total of 148 prostate cancer patients were randomized 1:1 to receive either prophylactic silodosin on day one of EBRT or the occurrence of RI-LUTSs. LUTSs were quantified using the international prostate symptom score (IPSS) at regular intervals during the study. The primary endpoint was the change in the IPSS from baseline to the last day of radiotherapy (RT). Secondary endpoints included changes in IPSS from baseline to 4 weeks and 12 weeks after the start of RT. Results: Patient demographics, baseline IPSS, and prescribed radiation doses were balanced between arms. On the last day of RT, the mean IPSS was 14.8 (SD 7.6) in the experimental arm and 15.7 (SD 8.5) in the control arm (p= 0.40). There were no significant differences in IPSSs between the study arms in the intention-to-treat (ITT) analysis at baseline, the last day of RT, and 4 and 12 weeks post-RT. Conclusion: Prophylactic α-blockers were not effective at significantly reducing RI-LUTSs in prostate cancer patients treated with EBRT. Treating patients with α-blockers at the onset of RI-LUTSs will avoid unnecessary drug exposure and toxicity.