ASCO GU 2020: Transcriptome Profiling of NRG Oncology/RTOG 9601: Validation of a Prognostic Genomic Classifier in Salvage Radiotherapy Prostate Cancer Patients from a Prospective Randomized Trial

San Francisco, California (UroToday.com) At the oral abstract session on prostate cancer at the 2020 Genitourinary Cancers Symposium, Dr. Felix Feng presented the performance of the Decipher™ genomic classifier applied to patients enrolled in the NRG Oncology/RTOG 9601 randomized controlled trial.

In RTOG 9601, 760 patients who were planned to undergo salvage radiation therapy following biochemical recurrence after radical prostatectomy were randomized to either 24 months of 150mg of bicalutamide or placebo. The primary results of this trial were published in the New England Journal of Medicine in February 2017 and demonstrated an approximate 5% risk reduction in overall mortality favoring the bicalutamide group compared to the placebo group after 12 years of follow up (OS 76.3% vs 71.3%, HR 0.77 0.59-0.99). Subgroup analysis demonstrated that patients with higher PSAs at baseline benefitted more from the addition of bicalutamide.

In this study, formalin-fixed paraffin-embedded radical prostatectomy specimens from patients enrolled in RTOG 9601 underwent central review and RNA was extracted from the highest-grade tumor in the specimen and subjected to the Decipher clinical assay.  Regression was performed to determine the predictive ability of the Decipher score on distant metastasis (primary outcome) as well as prostate-cancer specific mortality and overall survival (secondary outcomes).

352 of the 760 patients had specimens of sufficient quality for genomic classifier (GC) scoring. This was affected in part by the fact that many specimens were ~20 years old and had been stored at room temperature.

The GC score, which is a continuous value from 0-1, was found to significantly predict DM (HR 1.19 [95%CI 1.06-1.35], p=0.003), PCSM (HR 1.37 [95%CI 1.18-1.61], p<0.001), and OS (HR 1.16 [95%CI 1.06-1.28], p=0.002) independent of age, race, Gleason score, T-stage, margin status, entry PSA, and treatment arm.

Further, the GC score was found to modify the beneficial effect of bicalutamide noted in the overall study. In patients with low GC scores (defined using the pre-defined commercially-locked cutoff of GC score) bicalutamide was only found to confer a 2.4% improvement in 12-year overall survival compared to an 8.9% survival improvement in a patient with intermediate or high GC scores. This is likely because fewer patients with low GC scores were destined to develop metastatic prostate cancer regardless of therapy, therefore fewer of these patients benefitted from more aggressive therapy with a combination of radiation and hormones vs radiation alone.

Decipher has already been validated as an independent predictor of the development of metastatic prostate cancer after radical prostatectomy in one meta-analysis of several cohort studies.1 This study reinforces this finding. Given that it adds prognostic information independent from other clinicopathologic factors, Decipher may help clinicians and patients decide on the aggressiveness of adjuvant and salvage therapy. However, as Dr. Daniel Lin pointed out in his invited commentary in this session, while the Decipher score adds information to the other variables, its predictive strength certainly does not overwhelm them. In fact, the effect size of each of the other significant variables in the model for prostate cancer specific mortality was actually larger than that of Decipher. (Decipher HR 1.39, treatment vs placebo 0.53, Gleason score >=8 2.53,  entry PSA 1.37) This is consistent with a prior paper published by Karnes et al which showed only marginal benefit of adding Decipher to clinical data in predicting PCSM.2 Thus, it is worth considering whether clinicopathologic variables provide adequate information to guide treatment decisions prior to performing GC scoring.

Presented by: Felix Feng, MD, Associate Professor of Radiation Oncology; Urology; and Medicine, Vice Chair for Faculty Development and Director of Translational Research, Department of Radiation Oncology, University of California of San Francisco

Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA @mcstroth at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. Spratt DE, Yousefi K, Deheshi S, et al. Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease. J Clin Oncol. 2017;35(18):1991-1998.
  2. Karnes RJ, Choeurng V, Ross AE, et al. Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features. Eur Urol. 2018;73(2):168-175.
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