130 Background: The low α/β ratio of prostate cancer (PrCa) is well established. However, stereotactic hypofractionated radiotherapy (SRT) has been investigated primarily in highly selected patient populations with low-intermediate risk disease. We performed a clinical trial of SRT delivered in once-weekly fractions on an unselected cohort of patients with non-metastatic PrCa. Methods: In this Phase I/II study 30 patients with non-metastatic PrCa (multiparametric MRI cT1-4N0, M0, Gleason 6-10, PSA < = 60 ng/ml) were treated with SRT to a prescription dose of 35Gy in 5 fractions delivered once a week (overall treatment time 29 days). Elective nodal RT at 25Gy/5Fr was delivered in patients high-risk by NCCN criteria, and androgen deprivation therapy given to intermediate and high-risk patients. SRT was planned using volumetric intensity modulated arc therapy (VMAT) or Helical Tomotherapy (HT) with pre-defined dose-criteria. The primary endpoint was acute toxicity NCI CTC v4, and secondary endpoints were biochemical control and late toxicity. Results: Thirty patients completed treatment per-protocol. Stage T3, Gleason 8-10, and PSA > 10 was seen in 18 (60%), 7 (23%) and 24 (80%) respectively. Overall 20 (66.7%) were high-risk. Median of Mean PTV dose was 36Gy, and normal tissue constraints could be met in all patients (Table). Acute urinary toxicities (Gr 0: 1; Gr 1: 27; Gr 2: 1; Gr 3-4: 0) and acute rectal toxicities (Gr 0: 20; Gr 1: 10; Gr 2: 0; Gr 3-4: 0) were very modest. The mean IPSS scores at baseline, end of treatment and 3 months after treatment were 8.8, 14.7, and 9.9. With a median follow up of 23.7 months, the 2 year biochemical control was 96%. Late grade 2 rectal bleeding developed in 1 patient. Conclusions: Carefully planned stereotactic VMAT/HT based once-weekly SRT to a predominantly high-risk non-metastatic PrCa cohort was very well tolerated and found to be safe for clinical use. Preliminary biochemical control and late toxicity profiles are encouraging. Clinical trial information: CTRI/2016/02/006671. [Table: see text]