Clinical Performance of the ExoDx (EPI) Prostate Intelliscore Test to Predict High-grade Prostate Cancer at Initial Biopsy: A Pooled Analysis of Three Independent Prospective Studies.
Authors: Margolis Erik , Brown Gordon , Partin Alan , Carter Ballentine , McKiernan James , Tutrone Ronald , Torkler Phillipp , Tadigotla Vasisht , Noerholm Mikkel , Donovan Michael J , Skog Johan 
Published: December 2020

Abstract
BACKGROUND The ability to discriminate indolent from clinically significant prostate cancer (PC) in the initial biopsy setting remains an important health issue. ExoDx Prostate(IntelliScore) (EPI), is a non-invasive exosome based liquid biopsy test that quantifies three RNA targets in exosomes from urine. The EPI test is used to help stratify patients for risk of high grade prostate cancer, HGPC (≥ GG2 PC) in men 50 years or older with PSA in the gray zone (2–10 ng/mL). The EPI test has been extensively validated and is included in the NCCN guidelines for prostate cancer early detection. Here we present a pooled meta-analysis from three independent prospective validation studies in men presenting for initial biopsy decision. Age range and PSA level subgroups were also analyzed for EPI performance.METHODS Pooled data from two prospective multi-site validation studies and the control arm of a clinical utility study were analyzed. The data from these three independent trials is presented for men 50 years or older with PSA 2–10 ng/ml presenting for their initial prostate biopsy as well as a subgroup of patients between 55–69 years as recommended by the USPSTF (United States Preventative Services Task Force) and PSA greater than 3 ng/mL as per NCCN 2020 guidelines. Diagnostic needle biopsy outcomes were compared with the EPI score, PSA and both the Prostate Cancer Prevention Trial (PCPT 2.0) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators. 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, median PSA 5.2 ng/mL and 17% African ancestry. The positive biopsy rate was 52% for ≥ GG1, 30% ≥GG2 and 14% ≥GG3. The EPI AUC of 0.70 was superior to PSA (AUC:0.56), PCPTRC (AUC: 0.62), and ERSPC (AUC: 0.59), (all p-values < 0.001) for discriminating GG2 from GG1 and benign histology. The previously validated cut-point of 15.6 (or alternative 20) would avoid 23% (or 34%) of all prostate biopsies and 30% (or 43%) of “unnecessary” (benign or Gleason 6/GG1) biopsies, with an NPV of 90% (89%). Across the total cohort (n = 1212), only 2.3% (28/1212) or 3.8% (46/1212) of patients would experience delayed detection of ≥ GG2 at the < 15.6 or < 20 threshold, respectively and for GG3, 1% (12/1212) and 1.5% (19/1212) at either cut-point would be delayed. Comparable results were identified when either the USPSTF 55–69 year age limit or NCCN PSA greater than 3 ng/mL were applied.CONCLUSIONS EPI is a non-invasive, easy to use, urine exosome-RNA assay that has been validated across 3 independent prospective multi-center clinical trials with 1212 patients. The test can discriminate high-grade (≥GG2) from low-grade (GG1) cancer and benign disease and performs equally well in the larger cohort as well as across the USPSTF and NCCN restricted subgroups. EPI effectively guides the biopsy decision process and improves identification of HGPC independent of PSA and other standard of care factors.