From prostate specific antigen to genomic signatures: Advances in biomarkers for prostate cancer diagnosis and prognosis.

Prostate cancer is one of the most common malignancies in men worldwide. Therefore, there is an urgent need to develop accurate, accessible biomarkers for diagnosis, prognosis, and therapy monitoring. Tumor markers, which can be measured in blood, urine, or tissue, provide valuable information regarding tumor presence, progression, and response to treatment. This review provides a comprehensive overview of routinely used diagnostic and emerging biomarkers for prostate cancer, based on a systematic MEDLINE/PubMed search. Key biomarkers analyzed include PSA and its derivatives, PCA3, and TMPRSS2-ERG, as well as genomic tests such as Prolaris, Decipher, and ConfirmMDx, and liquid biopsy-based tests such as ExoDx Prostate and SelectMDx. This narrative review demonstrates that although PSA remains the mainstay of prostate cancer diagnosis, emerging molecular and genomic biomarkers are enhancing diagnostic specificity, refining risk stratification, and enabling more personalized patient care. The integration of routinely used and novel biomarkers can improve early detection, optimize treatment decisions, and ultimately improve outcomes of prostate cancer patients.

e17158 Background: The ExoDx urinary biomarker test has been validated for the investigation elevated prostate specific antigen (PSA) levels. The performance of this test in lieu of or in parallel with the radiographic “biomarker” multiparametric magnetic resonance imaging (mpMRI) has not been fully elucidated. The objective of the present study was to develop novel nomogram that incorporates mpMRI, ExoDx Prostate Intelliscore (EPI), patient demographics, and clinical information to assess a patient’s risk of having a clinically significant prostate biopsy (i.e. Gleason Grade Group ≥2) to optimize patient decision making regarding prostate biopsy. Methods: A retrospective study at a single academic medical center was conducted. Patients who underwent ExoDx urinary analysis, had mpMRI imaging, and had a prostate biopsy between 10/1/2019 and 07/31/2024 were included. Demographic data collected included age, race, insurance type/status. Clinical data collected included ExoDx Score (EPI) [continuous variable], multiparametric PI-RADS version 2.1 score, PSA, prostate volume, radiographic prostatitis, number of regions of interest on MRI, and adverse features such as extraprostatic extension, seminal vesicle invasion, and pelvic lymphadenopathy on mpMRI. Primary outcome of interest was clinically significant prostate cancer (i.e. ≥ GG2) on biopsy. Statistical tests of association were performed along with univariable and multivariable Cox regression analysis; independent predictors were screened in a stepwise regression for collinearity. Cross validation testing of the model was performed. Results: 387 patients had EPI scores, and 142 patients who underwent prostate biopsy were included for analysis after EPI score (p< 0.05), PIRADS >3 (p< 0.05), and prostate volume (p< 0.05) were independent prognostic factors in predicting an increased risk of clinically significant prostate cancer on biopsy. A nomogram was developed with accuracy of 69% (95% CI: 0.6072, 0.765), positive predictive value of 47.4%, and a negative predictive value of 72.4%. Conclusions: Our novel nomogram integrates independent urinary and radiographic biomarkers along with demographic information to predict clinically significant prostate cancer. The modest performance is likely due to modest sample size and would benefit from validation with a larger cohort.

Prostate cancer remains a leading malignancy among men in the United States. While prostate-specific antigen (PSA) screening improves early detection, it also leads to over-diagnosis and over-treatment. Biomarkers offer a promising solution for risk stratification and guiding treatment decisions. This review examines the cost-effectiveness of serum, urine, and tissue-based biomarkers to assess their impact on healthcare expenditures and clinical decision-making. Serum-based biomarkers like 4Kscore and PHI reduce unnecessary biopsies and healthcare costs. Urine-based biomarkers, including SelectMDx and ExoDx Prostate IntelliScore (EPI), have shown potential to optimize prostate cancer detection while being more cost-effective than some serum-based alternatives. Tissue-based biomarkers, such as OncotypeDx and Decipher, help in treatment selection, though their economic impact varies. Economic analyses suggest that biomarkers can enhance clinical decision-making while reducing healthcare expenditures, but real-world validation remains limited. Prostate cancer biomarkers improve risk stratification and may lower healthcare costs. However, variations in cost-effectiveness, reimbursement policies, and guideline recommendations limit widespread adoption. Prospective studies are needed to validate real-world cost savings and refine biomarker integration into clinical practice. Addressing financial and policy challenges is essential to ensure equitable access and maximize their impact on prostate cancer management.

P003 Defining the ExoDx Prostate (EPI) score for biopsy proven prostate cancer after MRI prostate

Clinical decisions based on the test results for prostate-specific antigen often result in overdiagnosis and overtreatment. Multiparametric magnetic resonance imaging (mpMRI) can be used to identify high-grade prostate cancer (HGPCa; Gleason score ≥3 + 4); however, certain limitations remain such as inter-reader variability and false negatives. The combination of mpMRI and prostate cancer (PCa) biomarkers (prostate-specific antigen density, Proclarix, TMPRSS2:ERG gene fusion, Michigan prostate score, ExoDX prostate intelliscore, four kallikrein score, select molecular diagnosis, prostate health index, and prostate health index density) demonstrates high accuracy in the diagnosis of HGPCa, ensuring that patients avoid unnecessary prostate biopsies with a low leakage rate. This manuscript describes the characteristics and diagnostic performance of each biomarker alone and in combination with mpMRI, with the intension to provide a basis for decision-making in the diagnosis and treatment of HGPCa. Additionally, we explored the applicability of the combination protocol to the Asian population.

Recognizing the limitations of prostate-specific antigen (PSA) screening and the morbidity of prostate biopsies, several blood- and urine-based biomarkers have been proposed for pre-biopsy risk stratification. These assays aim to reduce the frequency of unnecessary biopsies (i.e., negative or Grade Group 1 [GG1]) while maintaining highly sensitive detection of clinically significant cancer (GG ≥ 2) prostate cancer. We reviewed the literature describing the use of currently available blood- and urine-based biomarkers for detection of GG ≥ 2 cancer, including the Prostate Health Index (PHI), 4Kscore, MyProstateScore (MPS), SelectMDx, ExoDx Prostate Intelliscore (EPI), and IsoPSA. To facilitate clinical application, we focused on the use of biomarkers as a post-PSA secondary test prior to biopsy, as proposed in clinical guidelines. Our outcomes included test performance measures-sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV)-as well as clinical outcomes resulting from biomarker use (i.e., unnecessary biopsies avoided, GG ≥ 2 cancers missed). Contemporary validation data (2015-2023) reveal that currently available biomarkers provide ~15-50% specificity at a sensitivity of 90-95% for GG ≥ 2 PCa. Clinically, this indicates that secondary use of biomarker testing in men with elevated PSA could allow for avoidance of up to 15-50% of unnecessary prostate biopsies, while preserving detection of 90-95% of GG ≥ 2 cancers that would be detected under the traditional "biopsy all" approach. The contemporary literature further supports the proposed role of post-PSA biomarker testing to reduce the use of invasive biopsy while maintaining highly sensitive detection of GG ≥ 2 cancer. Questions remain regarding the optimal application of biomarkers in combination or in sequence with mpMRI.

We discussed the challenges associated with the clinical application of extracellular vesicles and summarized their potential impact on oncological clinical practice in urology. Despite extensive research on extracellular vesicles, their clinical applications remain limited; this is likely to be because of small study cohorts, a lack of large-scale analyses, and the impact of variable extraction and storage methods on analysis outcomes. However, promising results have emerged from clinical trials targeting urinary extracellular vesicles in prostate cancer using ExoDx Prostate Test. The ExoDx Prostate Test has demonstrated its efficacy in diagnosing prostate cancer in previous studies and is the only FDA-approved kit for this purpose. Moreover, recent trials have investigated the use of the ExoDx Prostate Test to determine the optimal timing for biopsies in prostate cancer patients undergoing active surveillance. We summarized recent studies on the potential of extracellular vesicles in the management of urological cancers. Particularly, the diagnosis of prostate cancer using the ExoDx Prostate Test has yielded positive results in several clinical trials. Additionally, while there are other studies suggesting its efficacy, most of these are based on retrospective analyses. These findings warrant further large-scale studies to optimize extracellular vesicle-based diagnostic and monitoring strategies. Although further research is required, extracellular vesicles would be attractive for early detection and surveillance.

e17090 Background: Prostate cancer screening relies on prostate-specific antigen, which may lead to unnecessary prostate biopsies. The ExoDx Prostate (EPI) test, a urinary exosome assay, has been developed for the detection of clinically significant (Gleason Grade Group ≥2) prostate cancer (csPCa) to improve specificity. This study analyzes the performance characteristics of EPI compared to/in concert with a multiparametric MRI (mpMRI)-based pathway at a single academic institution. Methods: Patients who underwent EPI testing between 10/2019 to 5/2023 were reviewed for EPI score, demographics, MRI characteristics, and biopsy results. Patients were categorized by EPI score (high risk ≥ 15.6 vs. low risk < 15.6). Outcome variables of biopsy and MRI were compared between EPI risk groups using Chi square and Mann Whitney-U test. Spearman correlation was used to estimate the correlation between EPI score and PI-RADS and Gleason score. Receiver operator curve (ROC) analysis assessed the performance of EPI and PI-RADS score for prediction of csPCa. An optimal cutoff value was determined for EPI using ROC, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed. Statistical comparisons were two-sided with a p-value <0.05 being statistically significant. Results: Of n=173 patients with EPI scores, 28.9% were low risk and 71.1% were high risk. EPI had weak correlation with PI-RADS score on prostate MRI (r = 0.30, p <0.001). An optimal EPI score cutoff for the detection of csPCa of 26.43 was determined (sensitivity 0.720, specificity 0.537, PPV 0.367, NPV 0.800). On ROC analysis, PI-RADS with score of ≥4 had better predictive performance for detecting csPCa with an Area Under the Curve (AUC) of 74.6% (sensitivity: 0.696, specificity: 0.721, PPV: 0.485, NPV: 0.862), versus an AUC of 63.1% with EPI testing. By utilizing a criteria of PI-RADS score ≥4 and EPI ≥ 26.43, we found improved PPV and specificity over either alone (PPV: 0.556 vs 0.485 vs 0.367, respectively) (specificity: 0.873 vs 0.721 vs 0.537, respectively). In addition, we found that with utilization of either PI-RADS score ≥4 or EPI ≥ 26.43, there was improved NPV and sensitivity (NPV: 0.962 vs 0.862 vs 0.800, respectively) (sensitivity: 0.957 vs 0.696 vs 0.720, respectively). Conclusions: Our study supports EPI testing as a way to assess risk for csPCa, ideally in combination with mpMRI, and also prompts reevaluation of 15.6 as an optimal cutoff EPI score.

MP41-04 EXOSOME BIOMARKER CLINICAL IMPACT ON TIMING AND DECISION TO HAVE A PROSTATE BIOPSY

MP41-07 UTILIZATION OF ExoDx PROSTATE TEST FOR PROSTATE CANCER RISK STRATIFICATION IN THE AFRICAN AMERICAN POPULATION

PD42-12 CLINICAL IMPACT OF AN INTEGRATED ExoDx PROSTATE BIOMARKER AND mpMRI FOR HGPCA RISK ASSESSMENT: PRACTICE PATTERNS, AND PERFORMANCE IN THE CLINIC

BPI24-026: Utilization of ExoDx Prostate Test for Prostate Cancer Risk Stratification in the African American Population.

Prostate cancer (PCa) is one of the most prevalent and deadly cancers among men, particularly affecting men of African descent and contributing significantly to cancer-related morbidity and mortality worldwide. The disease varies widely, from slow-developing forms to highly aggressive or potentially fatal variants. Accurate risk stratification is crucial for making therapeutic decisions and designing adequate clinical trials. This review assesses a broad spectrum of diagnostic and prognostic biomarkers, many of which are incorporated into clinical guidelines, including the Prostate Health Index (PHI), 4Kscore, STHLM3, PCA3, SelectMDx, ExoDx Prostate Intelliscore (EPI), and MiPS. It also highlights emerging biomarkers with preclinical support, such as urinary non-coding RNAs and DNA methylation patterns. Additionally, the review explores the role of tumor-associated microbiota in PCa, offering new insights into its potential contributions to disease understanding. By examining the latest advancements in PCa biomarkers, this review enhances understanding their roles in disease management.

BackgroundPatient outcomes were assessed based on a pre-biopsy ExoDx Prostate (EPI) score at 2.5 years of the 5-year follow-up of ongoing prostate biopsy Decision Impact Trial of the ExoDx Prostate (IntelliScore).MethodsProspective, blinded, randomized, multisite clinical utility study was conducted from June 2017 to May 2018 (NCT03235687). Urine samples were collected from 1049 men (≥50 years old) with a PSA 2–10 ng/mL being considered for a prostate biopsy. Patients were randomized to EPI vs. standard of care (SOC). All had an EPI test, but only EPI arm received results during biopsy decision process. Clinical outcomes, time to biopsy and pathology were assessed among low (<15.6) or high (≥15.6) EPI scores.ResultsAt 2.5 years, 833 patients had follow-up data. In the EPI arm, biopsy rates remained lower for low-risk EPI scores than high-risk EPI scores (44.6% vs 79.0%, p < 0.001), whereas biopsy rates were identical in SOC arm regardless of EPI score (59.6% vs 58.8%, p = 0.99). Also in the EPI arm, the average time from EPI testing to first biopsy was longer for low-risk EPI scores compared to high-risk EPI scores (216 vs. 69 days; p < 0.001). Similarly, the time to first biopsy was longer with EPI low-risk scores in EPI arm compared to EPI low-risk scores in SOC arm (216 vs 80 days; p < 0.001). At 2.5 years, patients with low-risk EPI scores from both arms had less HGPC than high-risk EPI score patients (7.9% vs 26.8%, p < 0.001) and the EPI arm found 21.8% more HGPC than the SOC arm.ConclusionsThis follow-up analysis captures subsequent biopsy outcomes and demonstrates that men receiving EPI low-risk scores (<15.6) significantly defer the time to first biopsy and remain at a very low pathologic risk by 2.5-years after the initial study. The EPI test risk stratification identified low-risk patients that were not found with the SOC.

MP17-10 DEVELOPMENT AND UTILIZATION OF AN AT HOME URINE EXOSOME BIOMARKER COLLECTION TEST KIT TO SUPPORT UROLOGIC TELEHEALTH

MP55-16 COMBINATION OF PRE-BIOPSY EXODX TESTING AND mpMRI IMPROVES PREDICTIVE POWER OF HIGH-GRADE PROSTATE CANCER

IntroductionIt is estimated that approximately 1.1 million cases of prostate cancer (PCa) are diagnosed in the world every year. In general, PCa is a slow-onset cancer and less than 10 percent of cases are detected in the metastatic phase. In order to identify patients at risk of suffering from clinically significant prostate cancer (csPCa), as well as to avoid unnecessary biopsies, overdiagnosis and overtreatment, a variety of molecular biomarker detection tests have been developed.MethodsWe undertook a systematic review with meta-analyses on the effectiveness of diagnostic tests based on biomarkers in blood or urine samples for the identification of men at risk of csPCa. A cost-effectiveness analysis was conducted using a decision tree model for the short term and a Markov model for the long term, both from the social and the National Health System perspectives. The effectiveness measure was quality-adjusted life years (QALYs). We ran extensive sensitivity analyses, including a probabilistic sensitivity analysis.ResultsSixty-five studies were included with a total of 34,287 participants. The diagnostic tests analyzed were: PHI, Progensa® PCA3, SelectMDx, MyProstateScore, 4Kscore®, TMPRSS2: ERG, Stockholm3, ExoDx Prostate IntelliScore and Proclarix®. All studies included biopsy as comparator. The sensitivity and specificity of diagnostic tests depended on the test itself and the threshold chosen, and ranged from 42 percent to 99 percent and from 13 percent to 87 percent, respectively. In the cost-effectiveness analysis, the alternative that includes the biomarker, specifically the SelectMDx, led to higher QALYs and healthcare costs with an estimated incremental cost-effectiveness ratio (ICER) of 6,640.21 EUR per QALY. The sensitivity analyses confirmed that the results were robust.ConclusionsBiomarker testing to select men at risk of csPCa who should undergo prostate biopsy can be a cost-effective strategy depending on its cost per determination and its sensitivity/specificity. The analyses carried out indicate that the SelectMDx biomarker is cost-effective at a cost of EUR 375 per determination.

PD11-08 A COMBINED BIOMARKER/MPMRI APPROACH PROVIDES ENHANCED CLINICAL INFORMATION PRIOR TO PROSTATE BIOPSY

Improved risk stratification of patients suspected of prostate cancer prior to biopsy continues to be an unmet clinical need. ExoDx Prostate (IntelliScore) “EPI” is a non-invasive urine test utilizing RNA from exosomes to provide a risk score that correlates with the likelihood of finding high grade prostate cancer at biopsy. Here, we present the results from a prospective clinical validation study of EPI-CE, a CE-marked in-vitro diagnostic (IVD) assay, specifically developed for use in European clinical laboratories. The study (NCT04720599) enrolled patients with ≥ 50 years, PSA 2–10 ng/mL, prior to MRI, who were scheduled for initial biopsy. First catch urine samples were collected from participants without prior digital rectal examination or prostate massage. Exosomal RNA was isolated and expression levels of three biomarkers ERG, PCA3 and SPDEF were analyzed according to the EPI-CE Instructions For Use. In the study cohort of N = 109 patients, EPI-CE was validated to have a Negative Predictive Value of 89%, a Sensitivity of 92% and a superior performance to two commonly used multiparametric risk calculators (PCPT and ERSPC) in both Receiver Operating Characteristics with a higher Area Under the Curve for EPI-CE 0.67 (95% CI 0.56–0.77) versus PCPT 0.59 (95% CI 0.47–0.71) and ERSPC 0.60 (95% CI 0.49–0.72) and higher Net Benefits analysis across a wide range of risk acceptance levels. This is the first clinical study reporting on the performance of EPI-CE. We demonstrate that EPI-CE provides information beyond standard clinical parameters and provides a better risk assessment prior to MRI, of patients suspected of prostate cancer, than the commonly used multiparametric risk calculators.