ObjectiveTo evaluate acute toxicity and quality of life (QOL) impact of ultra-hypofractionated whole pelvis radiotherapy (WPRT) compared to conventional WPRT fractionation post high-dose rate (HDR) prostate brachytherapy (BT). MethodsBLINDED FOR REVIEW is a phase 2, multi-institutional randomized controlled trial involving men with prostate-confined disease and NCCN unfavorable intermediate, high, or very-high-risk prostate cancer. Patients were randomly assigned to receive conventionally fractionated WPRT (standard arm) or ultra-hypofractionated WPRT (experimental arm) in a 1:1 ratio. All patients underwent radiotherapy with 15 Gy HDR-BT boost in a single fraction followed by WPRT delivered with conventional fractionation (45 Gy in 25 daily fractions or 46 Gy in 23 fractions) or ultra-hypofractionation (25 Gy in 5 fractions delivered on alternate days). Acute toxicities, measured during radiotherapy and at 6 weeks post-treatment, were assessed using the clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC-50) and International Prostate Symptom Score (IPSS). ResultsA total of 80 patients were enrolled and treated across three Canadian institutions. A total of 39 and 41 patients received external radiotherapy with conventionally fractionated and ultra-hypofractionated WPRT, respectively. All patients received androgen deprivation therapy, except for 2 patients treated in the ultra-hypofractionated arm. Baseline clinical characteristics were similar between the two arms, with 51 (63.8%) patients having high or very high-risk prostate cancer disease. Treatment was well tolerated with no significant differences in the rate of acute adverse events between arms. No grade 4 adverse events or treatment-related deaths were reported. Ultra-hypofractionated WPRT had a less detrimental impact in the EPIC-50 bowel total, function and bother domain scores when compared to conventional WPRT in the acute setting. On the contrary, more patients treated with ultra-hypofractionated WPRT reached the minimum clinical important difference on EPIC-50 urinary domains. No significant QOL differences between arms were noted in the sexual and hormonal domains. ConclusionUltra-hypofractionated WPRT following HDR-BT is a well-tolerated treatment strategy in the acute setting and leads to less detrimental impact on bowel QOL domains when compared to conventional WPRT.