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Original Investigation
February 11, 2021

Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial

Author Affiliations
  • 1Department of Radiation Oncology, UCSF Medical Center, San Francisco, California
  • 2Department of Medicine, UCSF Medical Center, San Francisco, California
  • 3Department of Urology, UCSF Medical Center, San Francisco, California
  • 4Decipher Biosciences, San Diego, California
  • 5Department of Radiation Oncology, University of Michigan, Ann Arbor
  • 6Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California
  • 7NRG Biorepository, Department of Pathology, UCSF Medical Center, San Francisco, California
  • 8Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts
  • 9Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida
  • 10Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
  • 11Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
  • 12Emmes Canada, Vancouver, British Columbia, Canada
  • 13NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
  • 14Department of Public Health, University of Chicago, Chicago, Illinois
  • 15Department of Medicine, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
  • 16Department of Oncology, University College London, London, United Kingdom
  • 17Department of Radiation Oncology, Centre Hospitalier de l’Université de Montréal-Notre Dame, Montreal, Quebec, Canada
  • 18Department of Radiation Oncology, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario, Canada
  • 19Department of Radiation Oncology, Froedtert and the Medical College of Wisconsin, Madison, Wisconsin
  • 20Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
  • 21Department of Radiation Oncology, WellSpan Health-York Cancer Center accruals under Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
  • 22Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland
  • 23Department of Oncology, Johns Hopkins University, Baltimore, Maryland
  • 24Department of Urology, Johns Hopkins University, Baltimore, Maryland
JAMA Oncol. 2021;7(4):544-552. doi:10.1001/jamaoncol.2020.7671
Key Points

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.

Abstract

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

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