Background: Androgen deprivation therapy (ADT) improves disease control in intermediate (IR) and high risk (HR) prostate cancer (PCa) treated with radiation therapy (RT), but also causes toxicity which may be worse in men of older age or with comorbidity. We hypothesized that dual agent ADT, replacing GnRH agonist for an oral 5-alpha-reductase inhibitor (5AR), would improve hormonal health-related quality of life (HRQOL) without compromising PCa outcomes. Methods: Patients with localized IR or HR PCa, age > 70 years and/or with Charlson comorbidity index (CCI) score > 2 were treated with bicalutamide and finasteride or dutasteride (oADT). A synchronous standard of care (SOC) cohort received bicalutamide and GnRH agonist. Median RT dose was 78 Gy. Dual agent ADT was given for 4 months (mo), while 5AR or GnRH agonist continued for an additional 2 years. The primary endpoint was the Expanded Prostate Cancer Index Composite (EPIC-26) hormonal HRQOL global score at 6 mo, with success defined as < 30% decline, requiring 40 men in the oADT group. Secondary endpoints included a log-rank comparison of freedom from biochemical failure (FFBF), and overall survival (OS). Results: Between 1/2011 and 8/2018, 40 and 30 men were prospectively enrolled in the oADT and SOC cohorts, respectively, with similar CCI scores > 2 (73% vs 66%, p=0.58), and age (mean 71, p=0.99). Median follow-up was 36 mo. Global scores for hormonal HRQOL at baseline, 6 mo, and 2 yr were 89, 88, 84 for the oADT group, and 92, 81, 83 for the SOC group; the declines from baseline to 6 mo (p=0.04) and 2 yr (p=0.05) were smaller in the oADT group. Sexual HRQOL was better preserved at 6 mo (p<0.01) in the oADT group, which maintained higher testosterone at 2 years (452 vs 44, p<0.01). There were no differences in urinary or bowel HRQOL. The 3-year FFBF was 90% vs 96% (p=0.83) and OS was 83 vs 86% (p=0.77) between the oADT and SOC groups, respectively. Conclusions: oADT improves hormonal and sexual HRQOL compared to SOC ADT in men age ≥ 70 or moderate comorbidity treated with RT. These groups could be further evaluated in a randomized comparison; post-ADT RNA expression to evaluate the relative biologic effects will be performed. Clinical trial information: NCT01342367