Background: Standard of care in VHR PCa is radiation therapy (RT) with 18-36 months (mos) of androgen-deprivation therapy (ADT). With this regimen, chronic ADT toxicity is significant and biochemical recurrence (BCR) frequent. We sought to improve tumor control and minimize toxicity with intensified short course ADT with dual androgen receptor signaling inhibitors (ARSI) and UHRT. Methods: 64 patients (pts) with VHR, N0 PCa were enrolled from 4 centers. VHR PCa was defined as Gleason score (GS) 9-10, >4 cores of GS 8 disease, or 2 high-risk features (including rT3/T4 disease). Treatment (tx) involved 6 mos of A, AA+P, and leuprolide with prostate/seminal vesicle-directed RT (7.5-8 Gy x 5 fractions). The primary endpoint was BCR defined as nadir PSA + 2ng/mL. Biochemical recurrence-free survival (bRFS) is reported herein. Our hypothesized reduction in BCR from 25% to 10% at 3 years (yrs) required 53 pts to provide a power of 0.84 and an alpha of 0.03. Undetectable PSA was defined as <0.10 ng/mL. Non-castrate testosterone (T) was a post-tx value >150 ng/mL. All analyses were intention-to-treat. Toxicity and health-related quality of life measures were evaluated using CTCAEv4.0 and the EPIC-26 questionnaire. Results: Baseline characteristics are summarized in the Table; 63 of 64 pts completed protocol tx. Median time to nadir PSA from tx start was 2 mos (range, 1-9); 63 of 64 pts (98.4%) achieved an undetectable nadir PSA. Median time to post-tx, non-castrate T was 6.5 mos (range, 2.5-25.5). Median follow-up (f/u) for pts without BCR was 30 mos (range, 15-44). Seven pts had BCR; 2-yr bRFS was 95.0% (95% CI, 89.7-100); 3-yr bRFS was 89.7% (95 CI, 81.0-99.3). For the 57 pts without BCR, 56 (98.2%) had T > 150ng/mL at last f/u; median PSA at last f/u was 0.10 ng/mL (IQR, <0.10-0.30); of these, 40 (70.2%) pts had PSAs ≤ 0.20 ng/mL with 24 (42.1%) undetectable. Fifteen pts experienced transient Grade 3 toxicities: 12 (18.8%) with hypertension and 3 with rash (4.7%). EPIC-26 scores for a subset of pts (n=21) at baseline and 12 mos showed no significant decline in urinary or bowel domains; declines in sexual (-11.9) and hormone (-5.7) domains met significance. Conclusions: Compared to historic controls with the long course ADT, AASUR demonstrated impressive 3-yr bRFS, rapid T recovery, and limited toxicities; the safety profile of this regimen was consistent with the known AE profile of the ARSI and RT. This regimen warrants further, randomized evaluation. Funded by Janssen Pharmaceuticals. Managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT02772588