Background: For men with unfavorable-risk non-metastatic (M0) prostate cancer (PC) the addition of docetaxel to radical prostatectomy (RP) or radiation therapy (RT) and androgen deprivation therapy (ADT) has been studied in 6 randomized controlled trials with negative or inconclusive results. Specifically, an overall survival (OS) benefit with a non-significant reduction in PC-specific mortality (PCSM) has been observed in two of the 6 studieswhere > 80% of the patients had high-grade PC. A plausible hypothesis for the OS benefit and a non-significant reduction in PCSM is that docetaxel reduces PCSM in the small subset of men with low prostate-specific antigen (PSA)-producing, high-grade PC that may be resistant to conventional ADT while also reducing non-PCSM by reducing death from RT-induced cancers. Given that docetaxel even at low doses (i.e. 20 mg/m²) is a potent radiosensitizer,it is plausible that it can sterilize cells that survive RT-induced damage and later develop into RT-induced cancers. Therefore, while docetaxel is not recommended when managing men with unfavorable-risk prostate cancer given inconclusive results from prior randomized trials, unstudied benefits may exist. Methods: This multicenter international randomized phase 3 trial (National Clinical Trial # 00116142) assigned 350 men with T1c-4N0M0 unfavorable-risk PC to receive ADT+RT and Docetaxel (60 mg/m² q3 weeks for 3 cycles before RT and 20 mg/m² weekly during RT) versus ADT+RT (1:1 ratio). Collection of data at each follow-up visit on second cancer incidence and survival status was recorded. We evaluated the treatment effect of adding docetaxel to ADT+RT on the primary endpoint of OS and the incidence of RT-induced cancers and explored whether the treatment effect impacted OS differed differently within PSA subgroups ( < 4, > 20 versus 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and known PC prognostic factors. Results: After a median follow-up of 10.2 years, 89 men died (25.43%); of these 42 from PC (47.19%). While OS was not significantly increased on the docetaxel arm [restricted mean survival time over 10-years was 9.11 versus 8.82 years with a difference of 0.29 (95% CI: -0.19, 0.76) years (p = 0.22)], significantly fewer RT-induced cancers were observed [10-year estimates: 0.61% versus 4.90%: age-adjusted HR of 0.13: 95% CI: 0.02, 0.97; p = 0.046]. For men with a PSA < 4 ng/mL versus 4-20 ng/mL the treatment effect of adding docetaxel to ADT+RT on OS differed significantly [Adjusted HR: 0.27, 1.51; p_interaction = 0.047] due to less PCSM on the docetaxel arm [0/13 (0.00%) versus 4/14 (28.57%)] among men with PSA < 4 ng/mL. Conclusions: Adding docetaxel to ADT+RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA < 4 ng/mL by reducing PCSM. Clinical trial information: NCT00116142