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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Feng reported receiving personal fees from Decipher, PFS Genomics, SerImmune, Celgene, Blue Earth Diagnostics, Astellas, Janssen, Roivant, Myovant, Genentech, Janssen Oncology, Sanofi, and Bayer; having a patent null pending during the conduct of the study; receiving grants from Zenith Epigenetics; and being a founding member and having ownership interests in PFS Genomics. Ms Huang reported receiving employee compensation from Decipher Biosciences Inc during the conduct of the study. Dr Spratt reported receiving personal fees from AstraZeneca, Janssen, BlueEarth; receiving grants from Janssen; and serving as an unpaid consultant at Decipher Bioscience outside the submitted work. Dr Zhao reported receiving grants from the Department of Defense; having a patent for genomic classifiers in prostate cancer pending with GenomeDx Biosciences and Celgene not directly related to this work; having a patent for a genomic classifier in breast cancer pending with PFS Genomics not directly related to this work; and having a family member with a leadership role at PFS Genomics, a breast cancer molecular diagnostics company, during the conduct of this study. Dr Sandler reported receiving grants from American College of Radiology-NRG Oncology; receiving personal fees from Janssen and Radiogel; and being a member of the American Society of Radiation Oncology Board of Directors during the conduct of this study. Dr Simko reported receiving grants from the National Cancer Institute and personal fees from Decipher Incorporated to his institution to cover the costs of specimen processing during the conduct of the study. Dr Davicioni reported serving as an employee of Decipher Biosciences during the conduct of the study and having a patent (US20170191133A1) pending to Decipher Biosciences. Dr Nguyen reported receiving personal fees from COTA, Ferring, Dendreon, Blue Earth Diagnostics, Myovant, and Boston Scientific; grants and personal fees from Astellas, Bayer, and Janssen; and personal fees and equity from Augmenix outside the submitted work. Dr Efstathiou reported receiving personal fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Taris Biomedical, Janssen, Bayer Healthcare, and Roivant Pharma outside the submitted work. Dr Dicker reported receiving personal fees from EMD Serono, personal fees from Oncohost, personal fees from Self Care Catalyst, Cybrexa, Janssen, ThirdBridge, Roche, Varian, Albert Einstein, Wilson Socini, Accordant, Envisnio, and Noxopharm; grants and nonfinancial support from NRG Oncology; and grants from the National Cancer Institute and the Prostate Cancer Foundation outside the submitted work. Ms Todorovic reported serving as an employee of Decipher Biosciences Inc during the conduct of the study. Ms Margrave reported being an employee of Decipher Biosciences Inc during the conduct of the study. Dr Liu reported being an employee of Decipher Biosciences Inc during the conduct of the study. Dr Thompson reported that his employer (Emmes Canada) is a contract research organization contracted by Decipher Biosciences to provide statistical consulting and analysis support during the conduct of the study. Dr Dignam reported receiving grants from the US National Cancer Institute during the conduct of the study and personal fees from Merck DMC membership, Celgene DMC membership, and Janssen outside the submitted work. Dr Sweeney reported receiving grants and personal fees from Sanofi, AstraZeneca, Pfizer, Astellas, Bayer, and Janssen; personal fees from Genentech/Roche; and nonfinancial support from Decipher outside the submitted work. Dr Sweeney also reported having a patent to TTP as a biomarker of lethal prostate cancer issued and licensed during the conduct of the study. Dr Attard reported performing uncompensated collaborative research with Decipher Biosciences that could result in IP generation during the conduct of the study. Dr Lukka reported receiving per case funding for patients from RTOG/NRG Oncology and receiving personal fees from AbbVie, Astellas, Janssen, Bayer, Sanofi, AstraZeneca, Tersera, and Ferring outside the submitted work. Dr Lukka reported being coordinator of GUROC (GU Radiation Oncologists of Canada). GUROC organizes meetings every 2 years and AstraZeneca, AbbVie, Tersera, Sanofi, Janssen, Astellas, Bayer, and Ferring have provided financial support to enable these meetings to occur. Dr Hall reported receiving unrestricted departmental research support and travel support related to MR Linac consortium leadership from Elekta and unrestricted departmental research support from Siemens Healthineers, Accuray, and Man Medical Technologies outside the submitted work. Dr Pugh reported receiving salary support paid to her institution from Millennium and salary support paid to her institution from Pfizer-Astellas outside the submitted work. Dr Tran reported receiving grants from Astellas Pharm, Bayer Healthcare, and RefleXion and personal fees from consulting from RefleXion and Ad Board from Noxopharm outside the submitted work. Dr Tran also reported having a patent (9114158, Compounds and Methods of Use in Ablative Radiotherapy) licensed to Natsar Pharm. No other disclosures were reported.

Figures

Figure 1.. Cumulative Incidence Estimates of Distant Metastasis (DM) and Prostate Cancer–Specific Mortality (PCSM) and Kaplan-Meier Estimates of Overall Survival (OS) by Genomic Classifier (GC) Risk Group

All patients with samples passing assay quality control metrics. The GC risk groups were categorized based on per-protocol cut points of 0.4 and 0.6. The numbers in parentheses are 95% CIs.

Figure 2.. Difference Between Arms, by Genomic Classifier (GC) Risk Group, for Predicted Rates of Distant Metastasis (DM), Prostate Cancer–Specific Mortality (PCSM), and Overall Survival (OS) at 12 Years

The top 3 panels (A) include all patients, whereas the bottom 3 panels (B) include early salvage patients only. Each bar height represents the difference in rates from subtracting the predicted rate in the treatment arm from the placebo arm (GC risk group: low = GC

Figure 3.. Prognostic Performance of Genomic Classifier (GC) for Distant Metastasis (DM) in Subgroups

The forest plot summarizes the univariable Cox regression results of the GC continuous score (hazard ratio reported per 0.1-unit increase) in the full cohort (indicated by Total) or subcohorts including arm (placebo or treatment), age (