Predicting high-grade prostate cancer at initial biopsy: clinical performance of the ExoDx (EPI) Prostate Intelliscore test in three independent prospective studies

Abstract

Background The ability to discriminate indolent from clinically significant prostate cancer (PC) at the initial biopsy remains a challenge. The ExoDx Prostate (IntelliScore) (EPI) test is a noninvasive liquid biopsy that quantifies three RNA targets in urine exosomes. The EPI test stratifies patients for risk of high-grade prostate cancer (HGPC; ≥ Grade Group 2 [GG] PC) in men ≥ 50 years with equivocal prostate-specific antigen (PSA) (2–10 ng/mL). Here, we present a pooled meta-analysis from three independent prospective-validation studies in men presenting for initial biopsy decision. Methods Pooled data from two prospective multi-site validation studies and the control arm of a clinical utility study were analyzed. Performance was evaluated using the area under the receiver-operating characteristic curve (AUC), negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity for discriminating ≥ GG2 from GG1 and benign pathology. Results The combined cohort (n = 1212) of initial-biopsy subjects had a median age of 63 years and median PSA of 5.2 ng/mL. The EPI AUC (0.70) was superior to PSA (0.56), Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) (0.62), and The European Randomized Study of Screening for Prostate Cancer (ERSPC) (0.59), (all p-values <0.001) for discriminating GG2 from GG1 and benign histology. The validated cutoff of 15.6 would avoid 23% of all prostate biopsies and 30% of “unnecessary” (benign or Gleason 6/GG1) biopsies, with an NPV of 90%. Conclusions EPI is a noninvasive, easy-to-use, urine exosome–RNA assay that has been validated across 3 independent prospective multicenter clinical trials with 1212 subjects. The test can discriminate high-grade (≥GG2) from low-grade (GG1) cancer and benign disease. EPI effectively guides the biopsy-decision process independent of PSA and other standard-of-care factors.

Validation of a CE-IVD, urine exosomal RNA expression assay for risk assessment of prostate cancer prior to biopsy

“…Similarly, in rank-based analysis, EPI-CE had the highest AUC 0.67 followed by the multivariate risk models ERSPC AUC 0.60 and PCPT AUC 0.59 and PSA with AUC 0.54, although none of these comparisons reached statistical significance. The 95% Confidence Interval of the AUC of EPI-CE was 0.56–0.77 in this study, indicating that at the current cohort size the natural variability of the data set is well within the range of the 0.70 that would be expected based on previous publications of EPI performance 2 – 5 . Further, as demonstrated in this publication of EPI-CE as well as the previous publications on EPI, the performance is consistently superior to existing alternatives, i.e., the multiparametric risk calculators.…”

“…We previously published on the development of a urine exosome gene expression test, ExoDx Prostate (Intelli-Score) (EPI-LDT, Exosome Diagnostics, Waltham, MA 02451, USA), which consistently outperforms the multivariable risk prediction models in identifying high-grade PCa (HGPCa) of Grade Group (GG) 2 or greater in studies in the US 2 – 5 . The EPI test relies on exosomes, which are small lipid bilayer vesicles secreted from living cells.…”

Pre-diagnosis urine exosomal RNA (ExoDx EPI score) is associated with post-prostatectomy pathology outcome

“…Exosomes contain RNA, DNA, and proteins and are particularly useful for RNA expression profiling given their protected microanatomic environment, which preserves the RNA [6]. The EPI test has been validated in multiple prospective clinical studies to assess the risk of high-grade PC (≥ GG2) in men with an equivocal PSA (2-10 ng/mL), prior to initial or repeat prostate biopsy [7][8][9][10][11]. In this setting, EPI demonstrated both a high negative predictive value (NPV) of 91.3% (≥ GG2) and 97% (≥ GG3) and a sensitivity of 92% at a cut point of 15.6 [7,8].…”

Biomarkers for prostate cancer detection and risk stratification

“…In this combined cohort, 17% identified as African American, but no distinct studies have yet been done to specifically evaluate the performance of the test in a racially diverse population. 42 …”