Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED study.

Abstract

BACKGROUND\nThe phase III CHAARTED trial established upfront androgen deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined.\n\n\nPATIENTS AND METHODS\nWhole transcriptomic profiling was performed on primary prostate cancer (PC) tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVA) adjusted for age, ECOG status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration resistant prostate cancer (ttCRPC).\n\n\nRESULTS\nThe analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared to localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower AR activity (AR-A) and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT+D (OS: HR 0.45, p=0.007), in contrast to basal subtype which showed no OS benefit (HR 0.85, p=0.58), even in those with high volume disease. Higher Decipher risk and lower AR-A significantly were associated with poorer OS in MVA. Additionally, higher Decipher risk showed greater improvements in OS with ADT+D (HR 0.41, p=0.015).\n\n\nCONCLUSION\nThis study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof-of-concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.