Abstract
PURPOSE: Men with rising prostate-specific antigen (PSA) after radical prostatectomy (RP) may progress despite radiation and androgen-deprivation therapy (ADT). Tissue-based transcriptomic signatures can identify who may benefit from a more aggressive systemic approach. METHODS: We performed a retrospective analysis of a prospective phase II multicenter trial of enzalutamide, ADT, and salvage radiotherapy in men with rising PSA after RP. Tumor tissue was analyzed using the Decipher platform for gene expression, including a novel prostate subtyping classifier, PTEN loss, homologous recombination deficiency (HRD), and ADT response. Cox models were used to associate signature scores with progression-free survival (PFS). RESULTS: Of the 38 men enrolled, 31 had tissue with sufficient-quality RNA for genomic analysis. Luminal differentiated (LD) subtype tumors had the longest 3-year PFS at 89% compared with 19% in the luminal proliferating subtype. Men with signatures of PTEN loss (hazard ratio [HR], 1.32; 95% CI, 1.07 to 1.64; P = .01) or HRD (HR, 1.21; 95% CI, 1.05 to 1.39; P = .009) had worse PFS, while those with higher ADT response signature scores (HR, 0.75; 95% CI, 0.61 to 0.94; P = .01) were associated with improved PFS. Analysis of these signatures in a large cohort (n = 5,330) of RP samples from patients with biochemical recurrence found that these signatures provide complementary information related to outcomes with salvage radiation. CONCLUSION: Despite aggressive systemic therapy with salvage radiation, nearly 50% of high-risk men relapse within 3 years. We show that LD and higher ADT sensitivity tumors had favorable outcomes. Those with a luminal proliferating subtype, PTEN loss, and/or HRD signatures had poor outcomes despite ADT/radiation and enzalutamide and may benefit from alternative approaches.