Multi-omics profiling of residual cancer burden after neoadjuvant hormonal therapy guides subtype-directed treatment in high-risk and locally advanced prostate cancer.

245 Background: Residual cancer burden (RCB) in patients failing to achieve pathological complete response (non-pCR) after neoadjuvant hormonal therapy (NHT) are a major cause of recurrence for high-risk localized and locally advanced prostate cancer (HRLPC). This study aimed to identify molecular subtypes of residual cancer and develop a precision framework to guide treatment of HRLPC. Methods: We performed integrated genomic, transcriptomic, proteomic, and N-glycoproteomic profiling of residual cancers from 138 HRLPC cases treated 3-6 months of ADT+ARPIs NHT. A molecular ssGSEA classification model was developed and translated into a clinically applicable immunohistochemistry (IHC)-based stratification scheme. Patient-derived organoids (PDOs) representing each molecular subtype were established and characterized, followed by drug sensitivity assays to validate potential therapeutic targets. Results: Three subtypes were characterized: C1 (AR and MYC signaling activation, poorest prognosis), C2 (upregulation of JAK-STAT pathway and high sialylation), and C3 (intermediate). A proteomic molecular classification model based on ssGSEA was constructed. Key biomarkers (CANT1, MRE11 for C1; CD8A, GSDME for C2) were identified, and developed an IHC-based classification strategy. The consistency between the ssGSEA and IHC model was validated (retrospective: Cohen’s Kappa = 0.719; prospective: Cohen’s Kappa = 0.747). PDOs representing C1–C3 subtypes were established for target prediction and drug validation, revealing the therapeutic potential of BETi for C1 and JAKi for C2. Conclusions: This study comprehensively elucidated the molecular characteristics of RCB in HRLPC after NHT, established a clinically translatable classification system, and proposed subtype-guided precision therapeutic strategies.