PCa Commentary | Volume 207 – November 2025

Posted by Edward Weber, MD | November 2025

The Emergence of Genomic Classifiers in Risk Stratification for Management of Prostate Cancer

Increasingly, there have been advances in refining stratifications to better guide treatment decisions. Analysis of a cancer’s gene expression provides insight into a tumor’s behavior and aggressiveness, matching a therapy’s appropriateness, and allowing avoidance of unnecessary toxicity, inconvenience, and expense. This tailoring might indicate, for example, that adjuvant hormone suppression would be of minimal benefit or that chemotherapy is not appropriate.

Decipher has emerged as an alternate risk stratification algorithm to the long-established NCCN Clinical Practice Guidelines, first published in 1998, to guide the standard of care and provide risk stratification to improve cancer treatment outcomes. The NCCN guidelines are based on clinical data such as PSA and Gleason Grade, type of primary therapy, stage at diagnosis, lymph node status, persistence of PSA after primary therapy, and have been a standard reference source.

In contrast, the tissue-based genomic classifiers, Decipher, Prolaris, Oncotype DX, and Genomic Prostate Score are genomic panels comprised of molecular markers that characterize an individual’s cancer’s aggressiveness. The results of the two approaches are similar but not identical: The NCCN offers management guidance while the genomic classifiers are predictive of an individual’s therapy outcome based on their tumor’s aggressiveness. Decipher was chosen for discussion because it has had the most extensive validation.

What is Decipher:

Decipher is a commercially available panel of 22 RNA biomarkers that control cellular proliferation, cancer cell invasiveness, androgen receptor activity, immune modulation, and tumor suppression. The assay is performed on tissue. Results are reported on a continuous scale, low risk to high risk, of 0 – 1.0. The Decipher assay provides a percentage probability of the risk of metastases within 5 years and the risk of prostate cancer-specific mortality within 10 years. The sensitivity of the Decipher assay lies in its capacity to identify molecular variations resulting from tumor heterogeneity, distinctions not captured in standard D’Amico categories of low-, intermediate-, and high-risk. The NCCN endorses roles for the Decipher test. The assay cost is between $3000 and $5000, but it is approved and covered by Medicare.

Three Examples of Applications of Decipher in Clinical Management Decisions:

1. DecipherUse When Considering Active Surveillance: Active Surveillance is considered appropriate for men diagnosed with GG1 (Gleason Score 3+3) and GG2 (3+4 with a low amount, ~5% of Gleason pattern 4). This restriction is suggested to avoid the early stage progression during AS requiring treatment.

   Press et al., (Eur Urol Open Sci. 2022) studied 133 men undergoing AS, 76% with GG1, 24% GG2. “The Decipher genomic classifier score was associated with short-term Gleason upgrading among patients with GG1 during active surveillance but not with GG2 disease. This finding is consistent with the heterogeneity among men with low-risk GG1 disease, where ~1 man out of 6 is upgraded from biopsy GG1 to a higher grade at prostatectomy. Men within the GG1 group would be good candidates for Decipher assessment.

2. Decipher and ArteraAI when considering the relative benefit from the addition and duration of ADT to radiation therapy following prostatectomy. Recurrence after prostatectomy is unfortunately common — ~30 – 40 %, largely due to the heterogeneity of men with low-grade Gleason Scores selected for surgery. Salvage radiation post-surgery can prolong disease-free status but may not prolong survival. The question then arises as to whether adjuvant hormone therapy would be sufficiently beneficial in this situation to offset the well-recognized adverse effects of testosterone suppression. The result of a tissue-based Decipher test can give prognostic guidance. A low risk for recurrence score (<.45) can inform a patient/clinician discussion about the inclusion of  ADT. The NCCN endorses the role of Decipher in the decision.

   ArteraAI Prostate Test: (Commercially Available. Access online at ArteraAI Prostate Test). [Discussed in the PCa Commentary, Vol #196 – click link pca-commentary-196 to follow or visit https://prostatecancerfree.org/prostate-cancer-news].

   The test is tissue-based on the prostatectomy specimen and submitted by the pathologist for analysis to ArteraAI. It predicts an individual patient’s likelihood of developing metastases at 10 years resulting from a short period of ADT. Results might suggest, for example, a 3% likelihood or perhaps a 34% likelihood. This data becomes the basis for patient/clinician discussion about management.

3. Decipher and Chemotherapy: Decipher can prospectively estimate the benefit of adding chemotherapy to ADT in treating metastatic castration-resistant prostate cancer. Based on a 10-year follow-up of the STAMPEDE trial involving 1523 men with high risk for recurrent cancer, Decipher can predict which men will benefit from the addition of chemotherapy to ADT alone. In men with a worrisome high Decipher score, the addition of chemotherapy offers a clear survival benefit, especially if the patient carries a mutation in the PTEN gene. (Grist, CELL. 2025)

BOTTOM LINE:

Decipher, a genomic classifier, offers a molecular assessment of a tumor’s aggressiveness and a more precise risk stratification than standard clinical data.

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