Prognostic validation of six androgen production, uptake, and conversion genes (APUC-6) in the CHAARTED prostate cancer trial.

5089 Background: Metastatic prostate cancer (mPC), whether synchronous or metachronous, remains incurable. Persistent androgen receptor (AR) activation promotes tumor progression and metastasis and impacts patient survival. A group of six genes ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1 ) involved in androgen production, uptake, and conversion (APUC-6) has been identified, exhibiting cohesive behavior that may define a subset of mPC with distinct clinical outcomes. Our study investigates the association of APUC-6 genes with clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and their potential to predict differential therapeutic responses. Methods: We analyzed APUC-6 and AR expression in microarray data from the phase 3 ECOG-ACRIN E3805 CHAARTED trial (n=160). Synchronous high-volume disease patients (n=113 or 70%) composed the majority of profiled cases. Patients were stratified into four subgroups based on APUC-6 and AR gene expression: APUC-6 high/ AR low (n=34), APUC-6 high/ AR high (n=6), APUC-6 low/ AR low (n=86) and APUC-6 low/ AR high (n=34). Key clinical outcomes included progression-free survival (PFS), time-to-castration resistance (ttCR) and overall survival (OS), with subgroup analyses based on the timing of metastasis. Results: Standard clinicopathologic factors were balanced between subgroups except lower proportion of patients with Gleason score ≥8 in APUC-6 high/ AR low subgroup (68.8% versus 81.0%-100% other subgroups).APUC-6 expression was significantly negatively correlated with AR expression (R= -0.26, p =0.001). Patients with APUC-6 high/ AR low expression represented a distinct subgroup that showed significantly improved PFS (median PFS 47.3 months, p <0.0001), ttCR (median ttCR 17.3 months, p =0.0011) and OS (median OS 58.1 months, p <0.0001) compared to other subgroups, including APUC-6 low/ AR high (PFS: median PFS 17.7 months, hazard ratio (HR) 0.43, Cl 0.22-0.82, p =0.0092; ttCR: median ttCR 12.0 months, HR=0.56, Cl 0.32-1, p =0.049; OS: median OS 29.4 months, HR 0.31, Cl 0.16-0.61, p =0.00032). Similar survival benefits of APUC-6 high/ AR low subgroup were observed within patients with synchronous high-volume disease (median PFS 23.1 months, p =0.0022; median ttCR 14.9 months, p =0.021; median OS 57.6 months, p =0.00038). Conclusions: In the CHAARTED mHSPC cohort, APUC-6 expression was inversely correlated with AR expression. The APUC-6 high/ AR low subgroup exhibited favorable PFS, ttCR and OS outcomes and maintained the survival benefits in synchronous high-volume disease. These findings suggest that high APUC-6 expression with low AR expression may define a favorable-risk mHSPC subgroup with distinct therapeutic implications.