BACKGROUND: The management of locally advanced prostate cancer (PCa) and oligometastatic prostate cancer (OMPCa) remains a clinical challenge. The heterogeneous nature of PCa prompts a need for precision treatment. This study aims to verify whether genomic biomarker-guided neoadjuvant therapy for locally advanced PCa and OMPCa can result in an improvement in the pathological responses and survival outcomes in a Chinese population. METHODS: In this open-label prospective phase II umbrella clinical trial, 40 patients will be enrolled. Next-generation sequencing data analysis of PCa tissues from the diagnostic needle biopsies will be performed. The genomically evaluable patients will be divided into 4 groups on the basis of genomic testing results, and receive 6 cycles of patient-tailored neoadjuvant systemic therapy targeted to alternative molecular pathways (including parmiparib, cisplatin, tislelizumab or docetaxel, respectively), and both in combination with rezvilutamide and goserelin microspheres. The primary endpoint is the rate of pathologic complete response. Secondary endpoints include rates of clinical complete response and pathological minimal residual disease (defined as residual tumor 5 mm or less), overall survival, progression-free survival and safety outcomes. DISCUSSION: SEGNO, to the best of our knowledge, is the first umbrella clinical trial designed to provide high-level evidence to support the implementation of genomic biomarker-guided neoadjuvant therapy for locally advanced PCa and OMPCa. TRIAL REGISTRATION: Clinicaltrial.gov, NCT06387056.