Background: Radical prostatectomy (RP) is associated with adverse surgical outcomes and an increased risk of disease progression in patients with high-risk/very high-risk localized prostate cancer (HRLPC/VHRLPC). This study aimed to evaluate the efficacy and safety of neoadjuvant darolutamide, a next-generation androgen receptor inhibitor, plus androgen deprivation therapy (ADT) for patients with HRLPC/VHRLPC undergoing RP. Methods: In this multicenter, single-arm phase II clinical trial, patients aged 18-75 year with HRLPC/VHRLPC (defined as Gleason ≥ 8 and/or cT3-4N0-1 and/or PSA ≥ 20 ng/mL). Patients with at least one of the following features were diagnosed with VHRLPC: cT3b-cT4, primary Gleason pattern 5, 2 or 3 high risk features, > 4 cores with Grade Group 4 or 5. Eligible patients received 6-month neoadjuvant darolutamide plus ADT followed by RP. The primary endpoint was pathological response rate (the proportion of patients with pathologic complete response [pCR] or minimal residual disease [MRD]). The secondary endpoints included safety, PSA progression-free survival, positive surgical margins rate, downstaging rate and PSA response rate. Results: Thirty patients were enrolled, and all patients had received robotic-assisted RP. The median age was 71.0 (interquartile range [IQR], 65.2-73.0) years, and the median PSA level was 37.8 (IQR, 21.0-94.7) ng/mL at baseline. A majority of the patients had VHRLPC (93.3%), while 6.7% had HRLPC, among whom N1 disease, cT3-4, Gleason 8-10, and PSA ≥ 20 ng/mL accounted for 26.7%, 86.7%, 90% and 77% of cases, respectively. The median prostate volume before RP was 19.4 mL (IQR, 15.6-28.4). Twenty-seven patients (90%) had undetectable PSA levels (＜0.01 ng/mL). The pCR rate was 6.7% and the MRD rate was 33.3%, resulting in a pathological response rate of 40.0%. Twenty patients (66.7%) achieved downstaging, and only four case (13.3%) had positive surgical margins. Eleven patients (36.6%) had extracapsular extension. The details of clinical and pathological outcome after neoadjuvant therapy are described in the Table. Conclusions: Darolutamide plus ADT for six months before RP improved clinical and pathological responses in men with HRLPC/VHRLPC, with favorable safety profile. Clinical trial information: NCT05249712.