Genomic enrichment using Decipher and PAM50 luminal B to optimize neoadjuvant immunotherapy strategies in high-risk prostate cancer.

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Background: Clinical risk tools incompletely capture biologic heterogeneity in prostate cancer (PCa), limiting enrichment for neoadjuvant trials. We evaluated whether integrating Decipher genomic risk with PAM50 luminal B subtype identifies a clinically aggressive and immunologically distinct subset suitable for biomarker-enriched therapeutic intensification. Methods: We analyzed 807 men undergoing radical prostatectomy with clinical Decipher testing. Marker-positive tumors were defined as Decipher intermediate/high/very high risk combined with PAM50 luminal B. Associations with biochemical recurrence (BCR) and distant metastasis (DM) were assessed using multivariable Cox models. Validation was performed in a commercial cohort (n=54,567). Pathway and immune signatures were evaluated. Multiplex immunohistochemistry was performed in paired pre-treatment biopsy and post-treated prostatectomy specimens from 15 marker-positive patients receiving neoadjuvant ADT ± AR signaling inhibitors. In vivo efficacy was assessed in MyC-CaP models treated with ADT + darolutamide + pembrolizumab. Results: Marker-positive tumors comprised 28.7% (232/807) of the cohort and were enriched for adverse pathology (81% vs 46%, p<0.001). BCR occurred in 38% vs 25% and DM in 19% vs 9% of marker-positive versus marker-negative high risk patients (both p<0.001), reflecting approximately two-fold metastasis enrichment. Marker-positive status independently predicted DM (HR 1.87, p=0.003). Marker-positive tumors demonstrated enrichment for PTEN loss, p53 mutation, and cell cycle progression signatures. Paired specimens demonstrated significant post-treatment increases in CD4+ and CD8+ T cells and PD-1/PD-L1–positive immune cells. In MyC-CaP models, ADT + darolutamide + pembrolizumab increased CD3+ infiltration and checkpoint expression compared with control and reduced tumor growth relative to monotherapy arms. Conclusions: Integrated Decipher and luminal B stratification identifies a biologically aggressive PCa subset with approximately two-fold higher metastasis risk and enrichment for immune-modifiable biology. These findings provide the rationale for an ongoing investigator-initiated phase II neoadjuvant trial of ADT + darolutamide + pembrolizumab followed by adjuvant pembrolizumab in molecularly selected high-risk PCa (GC>0.45 + luminal B; NCT07027124), with minimal residual disease (≤0.25 cm³) as the primary endpoint.