Genomic Classifier Performance in Intermediate-Risk Prostate Cancer: Results From NRG Oncology/RTOG 0126 Randomized Phase 3 Trial

Abstract

Purpose: Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up.

Methods and materials: After National Cancer Institute approval, biopsy slides were collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiation therapy without androgen deprivation therapy. RNA was extracted from the highest-grade tumor foci to generate the locked 22-gene GC model. The primary endpoint for this ancillary project was disease progression (composite of biochemical failure, local failure, distant metastasis, prostate cancer-specific mortality, and use of salvage therapy). Individual endpoints were also assessed. Fine-Gray or cause-specific Cox multivariable models were constructed adjusting for randomization arm and trial stratification factors.

Results: Two-hundred fifteen patient samples passed quality control for analysis. The median follow-up was 12.8 years (range, 2.4-17.7). On multivariable analysis, the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P = .04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P < .001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P = .01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P < .001). Ten-year distant metastasis in GC low-risk patients was 4% compared with 16% for GC high-risk patients. In patients with lower GC scores, the 10-year difference in metastasis-free survival rate between arms was -7%, compared with 21% for higher GC patients (P-interaction = .04).

Conclusions: This study represents the first validation of a biopsy-based gene expression classifier, assessing both its prognostic and predictive value, using data from a randomized phase 3 trial of intermediate-risk prostate cancer. Decipher improves risk stratification and can aid in treatment decision-making in men with intermediate-risk disease.

Trial registration: ClinicalTrials.gov NCT00033631.

Fig. 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram of the patient sample availability and sample quality from the NRG Oncology/RTOG 01–26-Decipher ancillary project. Abbreviations: DE = dose-escalated; GC = genomic classifier; QC = quality control; RT = radiation therapy.

Fig. 2.

Distribution of GC within clinical subgroups: (A) by randomization arm, (B) by T stage, (C) by Gleason pattern, and (D) by PSA at study entry. Abbreviations: 3D/IMRT = 3-dimensional/intensity modulated radiation therapy; GC = genomic classifier; PSA = prostate-specific antigen.

Fig. 3.

Prognostic performance of GC score in multivariable Fine-Gray or Cox proportional hazards models for all endpoints. Effect sizes of GC were reported per 0.1-unit increases and are reported for each endpoint from the appropriate model. Multivariable models were adjusted for the trial stratification variables and randomization arm (as main effect in Fine-Gray and as strata in Cox; see Table E3 for full model). *Indicates P < .05. ^†Indicates primary endpoint. ^‡Indicates Cox PH model. Abbreviations: ASTRO = American Society for Radiation Oncology; BF = biochemical failure; CI = confidence interval; GC = genomic classifier.

Fig. 4.

Interaction plot for GC risk group and randomization arm for the metastasis-free survival endpoint. Predicted 10-year metastasis-free survival from the Fine-Gray analysis of the interaction between GC risk group and randomization arm, with reported interaction term P value and (1-cumulative incidence) plots by GC risk group (see Table E8 for complete interaction model). Abbreviations: 3D/IMRT = 3-dimensional/intensity modulated radiation therapy; CI = confidence interval; GC = genomic classifier.