Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer

Abstract

Question Can a genomic biomarker estimate the risk of prostate cancer clinical end points in men who received salvage radiation for rising prostate-specific antigen levels after surgery? Findings In this ancillary study of 352 men randomized to placebo or hormone therapy in the NRG/RTOG 9601 clinical trial of salvage radiation, the Decipher genomic classifier was independently associated with the risk of metastasis, prostate cancer–specific mortality, and overall survival. Meaning These findings suggest that the Decipher genomic classifier is a promising biomarker to risk stratify men to better enable hormone therapy treatment decisions for biochemical recurrence of their prostate cancer after surgery. Importance Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer. Objective To validate the GC in the context of a randomized phase 3 trial. Design, Setting, and Participants This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network–approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer–specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019. Intervention Salvage radiotherapy (sRT) with or without 2 years of bicalutamide. Main Outcomes and Measures The preplanned primary end point of this study was the independent association of the GC with the development of DM. Results In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (−7.8% vs 4.6%). Conclusions and Relevance This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT. Trial Registration ClinicalTrials.gov identifier: NCT00002874 Identify all potential conflicts of interest that might be relevant to your comment. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. Err on the side of full disclosure. If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response. Not all submitted comments are published. Please see our commenting policy for details.