Background: Treatment paradigm for N+M0 PCa has evolved, with the advent of multiple options for upfront AA/Enz or RT in combination with conventional hormonal therapy (HT). However, the optimal treatment protocol remains undefined. We therefore conducted a prospective observational study of combination AA/Enz+RT in N+M0 PCa patients. Methods: Patients with biopsy-proven adenocarcinoma of the prostate and N+M0 by imaging (⁶⁸Ga-PSMA-PET or whole body MRI) were included. Exclusion criteria were 1) ECOG ≥2; 2) severe comorbidities; 3) cardiac event of <6 mo interval. Treatment protocol involved 18 mo of AA (1000 mg with 5 mg prednisolone once daily)/Enz (160 mg once daily)+HT (LHRH agonist/antagonist) in combination with RT to pelvis (54 Gy with simultaneous boost of 60-66 Gy in 27 fr) and prostate (78 Gy/39 fr); RT commenced 1-3 mo upon initiation of AA/Enz. Primary endpoint of this analysis was PSA of ≤0.1 ng/ml at 12 mo. Results: From Jun 2017-Sep 2019, 13 men were recruited; median follow-up duration was 14.0 mo (range 3.0-28.0 mo). Median age of the cohort was 67.0 y (IQR 61.0 – 69.0 y); 84.0% of men had GS8-10 disease, and median number of cN+ nodes was 2 (range 1-5 nodes). 11 received AA, and 2 received Enz. 53.8% (N = 7) and 69.2% (N = 9) of patients achieved a PSA nadir of ≤0.1 ng/ml at 6.0 and 12.0 mo, respectively; this contrasts against a propensity-matched cohort (N = 27) treated by HT+RT alone (33.3% and 51.9%, respectively). No biochemical recurrence was recorded at the time of analysis. 3 and 2 acute ≥G2 GU and GI toxicities were reported during RT. Late ≥G2 GU toxicities were observed in 2 men (G2 frequency). 2 patients experienced G2 fatigue and one with G2 transaminitis secondary to AA, with dose reduction. Germline genetic profiling with whole exome sequencing revealed two patients (15.4%) with BRCA2 frameshift mutations; interestingly, GU/GI RT toxicities were not observed in these patients. Conclusions: Our preliminary results suggest that combinatorial AA/Enz and high dose RT is tolerated and can induce a pronounced PSA response in low volume N+M0 PCa.