Objective To study the safety and efficacy of robot-assisted laparoscopic radical prostatectomy (RARP) combined with expanded pelvic lymph node dissection (ePLND) in treating very high-risk locally advanced prostate cancer, and to explore the effects of neoadjuvant hormone therapy (NHT) and neoadjuvant chemotherapy combined with hormone therapy (NCHT) on postoperative pathological features. Methods The clinical data of 156 patients with very high-risk locally advanced prostate cancer who underwent RARP+ePLND between Oct. 2015 and Mar. 2019 were retrospectively analyzed. The initial prostate-specific antigen (PSA), initial tumor TNM stage, Gleason score, neoadjuvant regimen, operation time, decrease of postoperative hemoglobin, perioperative complications, length of hospital stay, and postoperative pathology were recorded. Results The mean age of the patients was (67.9±6.9) years, with a median initial PSA of 56.5 ng/mL (range 8.4-629.0 ng/mL). Patients with Gleason score ≥ 8 accounted for 63.5% (99/156), clinical stage ≥ cT3 accounted for 95.5% (149/156), and 35.3% (55/156) of the patients had pelvic regional lymph node metastasis. The average operation time was (186.7±35.5) min, the decrease of postoperative hemoglobin was (18.8±9.9) g/L, and the median hospital stay was 5 days (3-66 days). Two patients (1.3%) developed rectal injury and three patients (1.9%) developed vascular injury during extended lymphadenectomy. In 64.1% (100/156) of patients, PSA decreased to less than 0.2 ng/mL after RARP+ePLND, 6.4% (10/156) of patients had complete pathological remission (pT0), and 25.6% (40/156) of patients had positive margins. There were 51.3% (80/156) patients achieving pathological downstaging and 15.4% (24/156) patients having pathological upgrading. Thirty-five patients were treated with RARP+ePLND without neoadjuvant therapy (non-NT group), 54 patients underwent four to six cycles of NHT (NHT group), and 67 patients underwent four to six cycles of NCHT (NCHT group). The initial PSA and TNM stage in the NCHT group were significantly higher than those in NHT group and non-NT group (both P<0.01), but there was no significant difference in perioperative complications among the three groups. In the NHT group and NCHT group, the patients with complete PSA response were 72.2% (39/54) and 82.1% (55/67), respectively, which was significantly higher than 17.1% (6/35) in non-NT group (P<0.01). In addition, 57.4% (31/54) of patients in the NHT group and 68.7% (46/67) in NCHT group showed a decrease in pathological stage, compared with 8.6% (3/35) in non-NT group (P<0.01). Conclusion RARP+ePLND is safe and effective in the treatment of very high-risk locally advanced prostate cancer, and preoperative neoadjuvant therapy may gain higher surgical cure rate and more significant pathological downstaging effect without increasing perioperative complications.