Background <p>The prognostic value of these pathological morphology alterations induced by neoadjuvant therapy in high-risk prostate cancer (PCa) patients is still unclear. Hence, this study retrospectively reviewed the data of 124 patients with high-risk PCa who underwent neoadjuvant therapy followed by radical prostatectomy (RP), and aimed to explore the prognostic value of pathological morphology alterations.</p> Methods <p>Data from 124 patients with high-risk PCa who underwent neoadjuvant therapy followed by RP were retrospectively reviewed. Pathological morphology alterations observed in RP specimens were independently recorded by two uropathologists, and the primary endpoint was biochemical progression-free survival (bPFS). Cox regression analyses were performed to explore independent predictors of bPFS, and a nomogram was developed. The C-index, calibration curves and decision curve analysis (DCA) were used to evaluate the performance of the nomogram.</p> Results <p>Among 124 patients, 66 patients (53.2%) were treated with neoadjuvant hormonal therapy (NHT), and 58 patients (46.8%) were treated with neoadjuvant chemohormonal therapy (NCHT). Moreover, 11 patients (8.9%) had a complete reduction in glandular density and diameter, and intraductal carcinoma of the prostate (IDC-P) was observed in 8 patients (6.5%). Cox regression revealed that NHT, pelvic lymph node (LN) metastasis, positive surgical margins, negative reduction in glandular density and diameter, and IDC-P were associated with worse bPFS (all <i>P</i> &lt; 0.05), and those factors were subsequently selected to develop a nomogram. The C-index was 0.813 (95% CI: 0.626–0.863), and time-dependent C-index were 0.902 (6 months), 0.882 (12 months), and 0.951 (24 months). The calibration curves showed a high consistency between the predicted and observed bPFS probabilities, and DCA confirmed the nomogram’s clinical utility across a range of threshold probabilities.</p> Conclusions <p>Pelvic LN metastasis, positive surgical margins and IDC-P were independent prognostic factors for high-risk PCa, and NCHT might significantly improve bPFS compared with the NHT. In addition, the degree of reduction in glandular density and diameter was also associated with bPFS, and the nomogram based on pathological morphology parameters-intended for postoperative risk stratification-might be helpful in clinical decision-making.</p> Trial registration <p>Retrospectively registered.</p>