Background: The conventional treatment backbone of N+ PCa has been hormonal therapy (HT) alone. Nonetheless, evidence from the STAMPEDE trial suggests that there could be survival benefit with the addition of local RT or AA, and there may be synergy between RT and AA in these advanced patients. We therefore conducted a prospective observational study to evaluate the efficacy of combination AA+HT+RT in patients with N+ PCa. Here, we report the preliminary biochemical response and toxicity data. Methods: Patients with N+M0/N+M1a, biopsy-proven adenocarcinoma of the prostate were enrolled. Patients were staged by ⁶⁸Ga-PSMA-PET or whole body MRI. Exclusion criteria were i) ECOG ≥2; ii) cardiac event of < 6 mo interval; iii) bone and visceral metastasis. Treatment protocol entailed 18 mo of combination AA (1000 mg plus 5 mg prednisolone once daily) and HT (LHRH agonist/antagonist); RT was delivered to the prostate (78 Gy) +/- pelvis (54 Gy with simultaneous boost of 60-66 Gy to grossly involved lymph nodes in M0 patients). This was matched against a control group that received long-term HT +/- RT (N = 38). Primary endpoint of this analysis was PSA ≤0.1 ng/ml at 6 mo; secondary endpoints were PSA ≤0.1 ng/ml, testosterone ≤0.7 nmol/l at 12 mo, and toxicity outcomes. Germline genetic profiling was performed in all patients. Results: From Feb 2017 to Aug 2019, 18 men were recruited to this study, with a median fu of 15 mo (range 6.0-35.0 mo). Median age was 66.0 y (IQR 62.0-71.0y); median baseline PSA was 18.2 ng/ml (range 3.0-272); 66.7% had GS 8-10 disease; and 22.2% had M1a disease. Combination AA+HT+RT achieved PSA of ≤0.1 ng/ml in 80.0% (N = 12) and 93.3% (N = 14) of patients at 6 mo and 12 mo, respectively, in contrast to 29.4% and 25.0% of patients who were treated with HT+RT and HT alone, respectively. We observed profound castration of 87.5% (N = 14) at 6 mo, and 91.7% (N = 11) at 12 mo. Four and 6 patients experienced acute G2 genitourinary and gastrointestinal toxicities during RT, respectively; 2 patients reported late G2 GU. One patient experienced G2 fatigue and G1 liver enzyme dysfunction, resulting in dose reduction of AA. Genetic testing revealed a patient with BRCA2 frameshift mutation; interestingly, this patient failed to achieve a PSA of ≤0.1 ng/ml at 12 mo. Conclusions: We demonstrate that combinatorial AA+HT and definitive RT is well tolerated, and yield a pronounced early PSA response in N+ PCa. Long-term data will inform if this early efficacy signal leads to improved survival in these patients.