Medical Policy

This document addresses the use of protein biomarkers for the screening, detection and management of prostate cancer, for example: IsoPSA^® (Cleveland Diagnostics, Inc.; Cleveland, OH), 4Kscore test (OPKO Diagnostics, LLC; Woburn, MA), Androgen Receptor Splice Variant-7 (AR-V7), MiCheck^® Prostate (Minomic International Ltd, Inc, Macquarie Park, Australia), and PanGIA Prostate (Genetics Institute of America; DelRay, FL). This document does not address prostate-specific antigen (PSA) testing.

Note: Please see the following related document(s) for additional information:

• CG-LAB-28 Prostate Specific Antigen Testing
• LAB.00015 Detection of Circulating Tumor Cells

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Investigational and Not Medically Necessary:

The use of protein biomarker tests for the screening, detection, and management of prostate cancer is considered investigational and not medically necessary.

This document describes clinical studies and expert recommendations, and when the use of protein biomarkers for the screening, detection and management of prostate cancer may be appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

This document looks at several blood-based tests that look for types of proteins that may help diagnose or manage prostate cancer. These include the 4Kscore test, IsoPSA, MiCheck and AR-V7. These tests aim to reduce the need for doctors to take tissue samples from the prostate (called a biopsy) by predicting cancer risk using blood samples. Each test has some benefits, but also drawbacks. While these tests have shown promise in early studies, they have not yet been proven to improve health or guide treatment better than current methods. As a result, they are not recommended for regular use. More research is needed to understand whether these tests can truly help people live longer or avoid unnecessary treatments.

What the Studies Show

The 4Kscore test looks at amounts of four blood proteins in the blood, along with age and other health details, to predict the chance of a person having prostate cancer. Some studies found it may help reduce unneeded biopsies while still catching high-risk cancers. However, most studies were paid for by the company that make the test, and many used previously collected blood samples instead of testing individuals in real time. The FDA approved the 4Kscore test but noted that it should only be used with other medical information and warned that it may mislead individuals or doctors if used alone. No studies have proven that using the test improves health or avoids unhelpful treatment.

The AR-V7 test looks for a specific protein linked to resistance to certain prostate cancer drugs. Studies show that people with this protein may not live as long and may respond differently to treatment. The currently available studies for AR-V7 have been small and varied in design making comparisons of their results difficult. Experts agree that larger, well-designed studies are needed before this test can be used to guide treatment.

IsoPSA is another FDA approved blood test that looks at different forms of the prostate-specific antigen (PSA) protein. One study found it may do a better job than regular PSA tests at spotting who might need a biopsy. Still, the long-term benefit of IsoPSA is unknown, and more research is needed to confirm its value in improving health outcomes.

MiCheck Prostate
The MiCheck Prostate test uses several blood proteins along with age and other health details to estimate the chance of having more serious prostate cancer. One study found it could help tell the difference between higher-risk and lower-risk cancer, but the results were based on computer modeling rather than use in the real world. There is no evidence showing that using MiCheck improves health outcomes or leads to better treatment decisions.

PanGIA Prostate
The PanGIA Prostate test uses a urine sample and special technology to look for patterns that may be linked to prostate cancer risk. Early studies suggest it may help identify cancer risk, but the research is limited and based on small or early-stage studies. There is no proof that using this test improves health or reduces the need for unnecessary procedures.

Is this clinically appropriate?

These tests are not appropriate because they have not been proven to improve health. While early studies show some promise, there is not enough high-quality research showing that these tests lead to better decisions or better health outcomes. Unnecessary or unproven tests can lead to needless worry, or to treatment that does not help. More research is needed to know if these tests improve health.

(Return to Description/Scope)

Summary

This document addresses the use of blood-based biomarkers for the screening, detection, and management of prostate cancer, including 4Kscore, IsoPSA, AR-V7, MiCheck Prostate, and PanGIA Prostate. The published evidence consists primarily of diagnostic accuracy studies, observational analyses, and modeling exercises that evaluate risk discrimination or changes in clinician decision-making rather than clinical outcomes. To date, no randomized trials or prospective studies have demonstrated that use of protein biomarker testing improves survival, reduces prostate cancer-related morbidity, or results in a net health benefit compared with standard approaches. Specialty society guidance does not recommend routine use of prostate cancer protein biomarkers, including guidance from the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) in collaboration with the Society of Urologic Oncology (SUO), which emphasize uncertainty in the current evidence base. Overall, the available literature does not support routine incorporation of protein biomarker testing into prostate cancer screening, detection, or management pathways.

Discussion

4Kscore

The 4Kscore test (OPKO Diagnostics, LLC) is a combination test that involves measures of fPSA (free prostate specific antigen), tPSA (total PSA), iPSA (intact PSA), and human kallikrein 2 (hK2) proteins. It combines data from blood levels of the four kallikrein proteins along with clinical information (age, digital rectal examination [DRE] findings, and a history of prior negative biopsy result). A proprietary statistical algorithm is then used to calculate a percentage risk (< 1% to > 95%) of having a Gleason score ≥ 7 if a prostate biopsy were to be performed.

An early industry-supported, published peer-reviewed clinical trial evaluating the use of the 4Kscore test was a study conducted by Vickers and colleagues (2008) that hypothesized if a multivariable model of four kallikrein proteins (tPSA, fPSA iPSA and hK2) could prognosticate the outcome of prostate biopsy in 740 unscreened males with elevated total PSA during the first round of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The ERSPC was a randomized trial which commenced in the 1990s to evaluate the effectiveness of prostate specific antigen (PSA) screening and its correlation with mortality. Their findings revealed that these four kallikrein proteins in a blood sample could forecast prostate biopsy results. Their sensitivity analysis prediction models were based on fresh tPSA and fPSA blood samples and thawed iPSA and hK2 blood (cryopreserved) samples. The results of the study demonstrated that adding fPSA and iPSa to the model improved the area under the curve (AUC) from 0.68 to 0.83 (p<0.0005) and from 0.72 to 0.84 (p<0.0005) for the laboratory and clinical models respectively, which reduces the probability of prostate biopsy. They proposed that the results would allow providers and their patients to discuss the pros and cons of biopsy compared to continued screening. In a second study by Vickers and colleagues (2010) the authors attempted to replicate their previous results in a large, independent, representative, population-based study involving 2914 individuals with elevated PSA > 3 ng/mL. The authors concluded that the use of a four-kallikrein panel improved the AUC from 0.64 to 0.76 and 0.70 and 0.78 respectively (p<0.001 for both AUCs) for models with and without DRE which conclusively can foretell prostate cancer biopsy results in males with elevated PSA. It was further concluded that the overall percentage of prostate biopsies conducted would be reduced with the use of the kallikrein panel.

Carlsson and colleagues (2013) sought to prove that the four-kallikrein panel statistical model could differentiate between diagnostically insignificant and aggressive disease on tissue specimens post-radical prostatectomy to determine the percentage of avoidable surgeries. This study was an arm of the Rotterdam ERSPC with 392 participants. Their findings suggested that the four kallikrein biomarkers in blood samples provided accurate results that could possibly decrease the percentage of avoidable treatment. The authors found that the addition of the kallikrein biomarker panel improved the base clinical model (incorporating age, stage, PSA, prior negative biopsy) with an AUC of 0.81 to an AUC of 0.84 (p<0.0005). They postulated that the application of this model in a clinical setting potentially reduces the rate of surgery by 135/1000 individuals overall and by 110/334 with inconsequential disease. They noted that proof existed for the clinical utility of the model for future use.

In a multi-center prospective study by Parekh and colleagues (2014), 1012 participants were scheduled for prostate biopsy where the Gleason score was ≥ 7 PCa. The AUC and decision curve analysis (DCA) prognosticated with probability comparisons to reduce the percentage of prostate biopsies and their subsequent impact on postponing diagnosis. The Gleason ≥ 7 PCa score was found in 231/1012 (23%) participants and confirmed a larger discrimination (AUC 0.82) and net benefit in comparison to a modified Prostate Cancer Prevention Trial (PCPT) Risk Calculator 2.0 standard of care model. It was estimated that a probable decrease of 30-58% in the number biopsies with a delayed diagnosis was in 1.3-4.7% of Gleason ≥ 7 PCa scores. The authors concluded that the 4Kscore test showed outstanding clinical utility in uncovering PCa and may be a useful instrument to identify at-risk males.

Bryant and colleagues (2015) conducted a retrospective study utilizing a two-sided statistical model with cryopreserved four kallikrein biomarker serum hypothesizing the test can predict biopsy outcome in 6129 participants (4765 for any Gleason grade at 10 core biopsy and 1364 to serve as impartial serum biomarkers). The authors selected males with elevated PSA (≥ 3.0 ng/mL) and who also participated in the Prostate Testing for Cancer and Treatment (Protec T) trial. The results of the four-kallikrein model showed improved cancer detection compared to with PSA and age variables. The AUC for kallikrein biomarkers was “0.719 (95% confidence interval [CI], 0.704 to 0.734) vs. 0.634 (95% CI, 0.617 to 0.651; p<0.001) for PSA and age for any-grade cancer and 0.820 (95% CI, 0.802 to 0.838) vs. 0.738 (95% CI, 0.716 to 0.761) for high-grade cancer.” For 1000 participants who underwent biopsies with PSA levels > 3.0 ng/mL, the model would lessen the rate of biopsy in 428 men, identify 119 high-grade cancers and defer diagnosis of 14/133 high-grade cancers using a 6% endpoint. The authors concluded that a kallikrein biomarker statistical model can prevent biopsies while postponing high-grade cancer diagnoses in few men.

A multi-institutional clinical utility study was performed by Konety and colleagues (2015) to evaluate the effect of the 4Kscore test in lieu of prostate biopsy for males referred to urologists for atypical PSA and/or DRE results. The study involved 611 participants in 35 United States academic and community settings. A 4Kscore test was ordered as part of the urology referral with concomitant findings stratified into low risk (< 7.5%), intermediate risk (7.5%-19.9%), and high risk (≥ 20%). The 4Kscore results affected the prostate biopsy decision in 88.7% of participants with a 64.6% decrease in biopsies in the low and intermediate risk males. Those males with a greater 4Kscore were more likely to have a biopsy (p<0.0001). Of the 171 participants biopsied the risk stratification was strongly correlated with pathology.

In a 2017 meta-analysis by Russo and colleagues, the authors reported on the diagnostic accuracy of prostate health index (PHI) and 4K panel for detection of prostate cancer and high-grade prostate cancer (high grade defined as Gleason score ≥ 7). A total of 28 studies that included 16,762 individuals were analyzed. For PHI for prostate cancer detection, the sensitivity was 0.89 and accuracy was 0.76. The 4K panel for prostate cancer showed a sensitivity of 0.74 and accuracy was 0.72. Regarding PHI, the negative predictive values ranged from 0.15 to 0.63, and positive predictive values ranged from 0.76 to 0.98. For the 4K panel, the negative predictive values ranged from 0.28 to 0.64, and positive predictive values ranged from 0.59 to 0.92. For detection of high-grade prostate cancer, the PHI showed a sensitivity of 0.93 and specificity of 0.34 with the 4K panel showing a sensitivity of 0.87 and specificity of 0.61. The accuracy for PHI was 0.82 and 0.81 for the 4K panel. Regarding PHI, the negative predictive values ranged from 0.05 to 0.31, and positive predictive values ranged from 0.88 to 0.99. For the 4K panel, the negative predictive values ranged from 0.08 to 0.43, and positive predictive values ranged from 0.95 to 0.99. While both the PHI and 4K panel showed fair diagnostic accuracy for overall prostate cancer detection with fair sensitivity and specificity, there is no demonstration that the use of such tests improves overall health outcomes or reduces other more invasive screening methods.

In a 2018 non-randomized, observational, prospective, blinded study by Borque-Fernando and colleagues, the authors analyzed the ability of the 4Kscore to predict tumor reclassification prospectively by upgrading at a confirmatory biopsy at 6 months from the initial biopsy. Inclusion criteria were participants with PSA ≤ 10 ng/mL, cT1c-T2a, Grade group (GG) 1, ≤ 2 cores, and ≤ 5 mm/50% length core involved. A total of 137 participants were analyzed (having received a confirmatory biopsy 6 months after an initial biopsy). After local and central pathological review, 18 participants were reclassified in grade at the confirmatory biopsy. Using 7.5% as cutoff for the 4Kscore, the authors found the sensitivity for finding Grade group ≥ 2 at confirmatory biopsy was 89% (95% CI, 65-99%) and specificity was 29%. The positive predictive value was 16% (95% CI, 9-25%) and negative predictive value 95% (95% CI, 82-99%). There were no reclassifications to Grade group 3 for the participants with 4Kscore below 7.5% and 2 participants who missed Grade group 2 were reclassified. The authors note the main limitations of this study are the relatively small number of participants and the low number of only 18 reclassification events. While the study was prospective and blinded, the authors also note that “our model has to be validated in another series of patients and also be studied in conjunction with other tools.”

A prospective study cohort enrolled 2872 men identified by screening biopsy to have a PSA ≥ 3.0. The predictive performance of the 4Kscore, Rotterdam Prostate Cancer Risk Calculator (RPCRC), and the combination of RPCRC with 4Kscore were analyzed in addition to the reduction of unnecessary biopsies and indolent prostate cancer. Clinically significant prostate cancer was present in 242 (8%) men, and indolent prostate cancer in 578 (20%). The 4Kscore and RPCRC had similarly high predictive performance (0.88 vs. 0.87; p=0.41). The 4Kscore-RPCRC combination improved performance to 0.89 compared to 4Kscore alone (p<0.01) and RPCRC alone (p<0.01). The RPCRC and 4Kscore reduced the number of unnecessary biopsies per 100 men at risk by 42 and 44, respectively, compared to a ≥ PSA 3.0, without increasing the number of missed clinically significant prostate cancers. The RPCRC-4Kscore combination resulted in a modest additional net reduction of 3.3 biopsies per 100 men at risk. Study limitations included lack of randomization and lack of long-term follow-up to characterize the impact of 4Kscore on clinically relevant outcomes (Verbeek, 2019).

In 2022, Rasmussen and colleagues conducted a retrospective cohort study in which 1476 individuals with 4Kscore measured prior to radical prostatectomy were enrolled. The study’s primary objective was to assess the 4Kscore’s ability to predict adverse pathology at time of prostatectomy and biochemical recurrence (BCR) compared to a clinical model derived from a historical cohort. Investigators determined that the 4Kscore increased discrimination for adverse pathology and prediction of BCR in all participants (delta AUC=0.009; 95% CI, 0.002-0.016 and delta C-index=0.014; 95% CI, 0.007-0.021, respectively). This discrimination was statistically driven by GG1 participant classifications for both primary outcomes. The study investigators conclude individuals with “GG1 prostate cancer and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC.”

In a U.S. Preventive Services Task Force (USPSTF) recommendation, the PSA-based screening for prostate cancer was given a C recommendation noting that:

For men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)-based screening for prostate cancer should be an individual one. Before deciding whether to be screened, men should have an opportunity to discuss the potential benefits and harms of screening with their clinician and to incorporate their values and preferences in the decision. (USPSTF, 2018).

An update of this recommendation is currently in progress.

In December 2021, the Food and Drug Administration (FDA) granted Premarket Approval (PMA, P190022) for commercial distribution of the 4Kscore test. The FDA-approved indication is for use with other patient information as an aid in the decision for prostate biopsy in men 45 years of age and older who have an abnormal age-specific total PSA and/or abnormal digital rectal exam (DRE), specifically: “The 4Kscore Test is intended to aid in detection of aggressive prostate cancer (Gleason score ≥ 7/Gleason Grade Group ≥ 2) for whom a biopsy would be recommended by a urologist, based on current standards of care before consideration of the 4Kscore Test. A 4Kscore < 5.0 is associated with decreased likelihood of a Gleason score ≥ 7 on biopsy.” The approval identified likelihood (probability) of Gleason Score ≥ 7 for four intervals of the 4Kscore results, including performance of the 4Kscore as described by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). No prospective data evaluating how the 4Kscore test affects net health outcomes, or how use of the 4Kscore affects health outcomes as compared to standard care was cited in the FDA approval. The FDA summary of safety and effectiveness data notes the following:

Based on the 4Kscore Test performance in the two pivotal clinical trials discussed […], the test provides probabilistic information that can inform the decision as to whether to perform a biopsy. As this information provides only probabilities, it is imperfect and there is a risk that this information could mislead the patient and physician to make a decision that ultimately does not have a favorable risk/benefit balance for the particular patient. This is mitigated by the standard practice of not using this information on its own, but rather, in conjunction with the other clinical information which include patient age, family history, results of genetic tests, PSA level, results of digital rectal examination, results of other laboratory tests, and importantly, patient preferences.

Androgen Receptor Splice Variant-7 (AR-V7)

The AR-V7 is a promising biomarker in the emergence and progression of metastatic castration-resistant prostate cancer. This Oncotype DX AR-V7 test is a blood test which identifies AR-V7 proteins in the nucleus of circulating tumor cells. Detection of the splice isoform AR-V7 in circulating tumor cells has been associated with resistance to commonly prescribed AR-targeted drugs.

In a 2019 study by Sharp and colleagues, the authors evaluated the reproducibility of AR-V7 testing, and associations with clinical characteristics, circulating tumor cell counts, tumor biopsy AR-V7 protein expression and overall survival. Using blood samples from 181 participants with metastatic castration-resistant prostate cancer and 136 participants with circulating tumor cell counts along with 58 participants with matched biopsies, AR-V7 status was determined. Overall, 95/277 samples were found to be positive for circulating tumor cells, 86/277 samples were positive for circulating tumor cells and negative for AR-V7, and 96/277 samples were positive for both circulating tumor cells and AR-V7. After taking baseline characteristics into consideration, the authors noted that overall survival was shorter in participants with positive circulating tumor cells and positive AR-V7 than in participants with negative circulating tumor cells. There was no evidence that participants with positive circulating tumor cells and positive AR-V7 had worse overall survival than participants with positive circulating tumor cells and negative AR-V7. The most significant limitation of this study was the heterogeneity of treatments received which did not allow the authors to evaluate AR-V7 expression as a predictive biomarker of response to treatment. While testing that determines circulating tumor cell AR-V7 status has the potential to impact treatment decisions, the authors note “Robust clinical qualification of these assays is required before their routine use.”

In a 2019 multicenter, prospective blinded validation study by Armstrong and colleagues, the authors sought to validate two circulating tumor cell AR-V7 assays in predicting progression-free survival and overall survival with abiraterone or enzalutamide in participants with metastatic castration-resistant prostate cancer. The authors evaluated the ability of pretreatment AR-V7 status in circulating tumor cells to predict treatment outcomes with abiraterone or enzalutamide by using the Johns Hopkins University modified-AdnaTest circulating tumor cell AR-V7 mRNA assay and the Epic Sciences circulating tumor cell nuclear-specific AR-V7 protein assays. The primary objective was to validate that participants with negative AR-V7 have prolonged progression-free survival with abiraterone or enzalutamide compared with participants with positive AR-V7 at the trial level. Using a cohort of 118 participants with high-risk metastatic castration-resistant prostate cancer, 55 were treated with abiraterone, 58 were treated with enzalutamide, and 5 received both therapies concurrently. Among surviving participants, the median follow-up time was 19.6 months. For the overall cohort, median progression-free survival was 5.8 months (95% CI, 4.1 to 7.6 months) and median overall survival (OS) was 20.3 months (95% CI, 17.0 to 27.2 months). At baseline, using the Johns Hopkins University assay, 28 participants were found to be AR-V7 positive, 88 participants were AR-V7 negative and 2 participants were unevaluable. Using the Epic protein-based assay, 11 participants were AR-V7 positive, 96 were AR-V7 negative, and 11 participants were unevaluable. With the Johns Hopkins University assay, the median progression-free survival for those who were AR-V7 positive was 3.1 months compared to 6.9 months for the participants who were AR-V7 negative. Median overall survival for participants who were AR-V7 positive was 10.8 months and 27.2 months for those who were AR-V7 negative. Using the Epic AR-V7 protein assay, the median progression-free survival for AR-V7 positive participants was 3.1 months and 6.1 months for the participants who were AR-V7 negative. The median overall survival for those who were AR-V7 positive was 8.4 months compared to 25.5 months for the participants who were AR-V7 negative. While this was a relatively large cohort, there were only 11 and 28 participants who tested positive for AR-V7 by the two different assays. The authors noted that larger controlled studies are needed to confirm the predictive value of AR-V7.

In a 2018 study by Scher and colleagues, the authors sought to determine whether AR-V7 protein in circulating tumor cells can determine overall survival in participants with metastatic castration-resistant prostate cancer who have been treated with taxanes compared to androgen receptor signal (ARS) inhibitors. A total of 142 blood samples (70 before initiation of therapy with an ARS inhibitor and 72 before initiation of therapy with a taxane) were used for the analysis in the second-line or greater therapy setting. The observed median survival time for participants who received ARS inhibitors was 16 months compared to 12.9 months for those who received taxanes. There was no significant difference in survival rates between the two groups. For the participants who were treated with ARS inhibitors, there was a more favorable survival outcome for those who were AR-V7 negative compared to those who were AR-V7 positive. For the participants who were AR-V7 negative and treated with ARS inhibitors, the median survival was 19.8 months and 12.8 months if they were treated with a taxane. The major limitation to this study was that participants were not prospectively randomized to treatment based on biomarker results. It is unknown how the biomarker status affects treatment decisions.

The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer (2025) state that the use of AR-V7 testing can be considered to assist with selection of the appropriate therapy for castration-resistant prostate cancer after progression on AR-targeted drugs.

IsoPSA

The IsoPSA test is a blood-based test designed to assess prostate cancer risk by detecting cancer-specific structural isoforms of PSA. In 2022, Klein and colleagues published results from a prospective, multicenter study of 888 individuals with a total PSA > 4 ng/ml scheduled for prostate biopsy. The primary study objective was to validate the diagnostic performance of previously established IsoPSA Index cutoffs, compare IsoPSA to total PSA and percent free PSA, and evaluate subgroups. The disease prevalence of high-grade prostate cancer was 37% and the prevalence of any prostate cancer was 59%; AUC was 0.783 (high-grade) and 0.770 (any-type). IsoPSA outperformed total PSA and percent free PSA on AUC, specificity, PPV and NPV. Based on the predetermined IsoPSA cutoffs, the study estimated that 46% of high-grade and 42% of any prostate cancer biopsies could be avoided in low-risk individuals. The clinical utility of this test remains to be established in randomized trials demonstrating the long-term impact on disease-specific outcomes.

In 2022, Scovell and colleagues published results from a real-world, observational clinical utility study to evaluate the impact of IsoPSA testing on provider recommendations for prostate biopsy and prostate MRI in individuals aged ≥ 50 years with total PSA ≥ 4 ng/mL undergoing evaluation for prostate cancer. A total of 900 individuals were enrolled across community-based and academic urology practices, with 734 meeting inclusion criteria for analysis. Following IsoPSA results, providers changed management recommendations in 60% of cases, resulting in a 55% net reduction in prostate biopsies recommended and a 9% reduction in MRI recommendations. Although provider recommendations demonstrated high concordance with IsoPSA results, the study did not assess adherence, biopsy outcomes, or long-term clinical endpoints, and no evidence of improved health outcomes were reported.

In 2023, Benidir and colleagues initiated a single-center retrospective study evaluating whether combining the IsoPSA serum assay with multiparametric prostate MRI using PI-RADS scoring could improve prediction of clinically significant prostate cancer at the time of biopsy in individuals with elevated PSA. The analysis included 207 individuals who underwent IsoPSA testing, prostate MRI within 1 year, and subsequent prostate biopsy. Both an elevated IsoPSA Index (≥ 6) and a PI-RADS 4-5 lesion were independent predictors of clinically significant prostate cancer (p=0.015 and p<0.001, respectively), and the combined IsoPSA + PI-RADS 4-5 model demonstrated improved discrimination compared with either modality alone (p<0.001). The predicted probability of clinically significant prostate cancer was < 5% in individuals with a low IsoPSA Index and negative or equivocal MRI (PI-RADS 1-3), leading the authors to suggest that biopsy might be safely omitted in select cases. This study is limited by its retrospective design, single-center setting, modest sample size, and absence of prospective evidence demonstrating improved clinical outcomes.

In 2025, Abdallah and colleagues initiated a single-center retrospective cohort study evaluating whether a baseline IsoPSA Index predicts the intermediate-term risk of developing clinically significant prostate cancer in individuals with elevated PSA. The study reviewed 1578 consecutive individuals who underwent IsoPSA testing between 2016 and 2022 and stratified outcomes by low (≤ 6) compared to high (> 6) baseline IsoPSA Index. Over a median follow-up of 24 months, individuals with a low baseline IsoPSA Index (n=541) demonstrated a substantially lower cumulative incidence of clinically significant prostate cancer at 12, 24, and 30 months compared with those with high IsoPSA Index values (0.4% vs. 5.9%, 2.5% vs. 31.7%, and 6.3% vs. 49.5%, respectively). While these findings suggest that a low IsoPSA Index is associated with a prolonged period of low clinically significant prostate cancer risk and may support reduced follow-up testing, the study is limited by its retrospective design, incomplete biopsy ascertainment, single-center setting, and lack of randomized evidence demonstrating improved health outcomes.

In 2025, the FDA granted PMA (P200048) of the IsoPSA Assay for use in conjunction with other information to aid in detection of high-grade prostate cancer in men ≥ 50 years of age, with total PSA levels between 4.0 and 10.0 ng/mL for whom a biopsy is being considered by a urologist based on current standard of care, before consideration of IsoPSA Assay results. The Summary of Safety and Effectiveness (FDA, 2025) includes the following statement: “Prostatic biopsy is required for the diagnosis of cancer” and the following warning and precautions:

• Patient with a falsely low IsoPSA Index ≤ 6.0 may not receive a necessary biopsy and therefore, could delay recognition of the presence of prostate cancer by the clinician, and could adversely delay the initiation of treatment. For patients with an IsoPSA index ≤ 6.0, the clinician should also consider obtaining mpMRI results to reduce the risk of missing high-grade prostate cancer (Grade Group ≥ 2; Gleason score ≥ 7). The IsoPSA Assay should not be used in patients with prostate mpMRI results with PIRADS score of 4-5.
• Patient with a falsely elevated IsoPSA Index could lead to a medical decision causing unnecessary biopsy.

FDA approval was primarily based on an industry-sponsored, unpublished prospective, multicenter clinical performance study to evaluate the IsoPSA assay as an aid in the detection of high-grade prostate cancer in individuals aged ≥ 50 years with total PSA levels of 4.0-10.0 ng/mL for whom a prostate biopsy was being considered. A total of 1422 individuals were enrolled across 14 U.S. community-based urology practices; 792 were clinically evaluable for study. Blood samples for IsoPSA testing were obtained within 30 days prior to standard-of-care prostate biopsy, and laboratory results were reported masked to biopsy pathology findings. The study demonstrated that IsoPSA provided discriminatory performance for the detection of Grade Group ≥ 2 prostate cancer and met predefined diagnostic performance endpoints required for FDA review, forming the basis for the FDA’s PMA as an adjunct to biopsy decision-making. However, the study was designed to assess analytical and clinical performance characteristics rather than clinical utility, and no evidence was generated demonstrating improved health outcomes, changes in management, or reductions in prostate cancer-related morbidity or mortality associated with IsoPSA testing.

MiCheck

In 2023, Shore and colleagues published a diagnostic development and validation study evaluating the MiCheck Prostate test, a multi-analyte blood assay combining total PSA, percent free PSA, HE4, and clinical factors to estimate the risk of clinically significant prostate cancer. The study characterized diagnostic performance using algorithmic modeling against biopsy outcomes and reported discrimination metrics for clinically significant disease. The analysis was designed to assess diagnostic performance and did not evaluate prospective clinical utility, observed changes in clinical management, or long-term outcomes.

In 2023, the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) published guidelines on the Early Detection of Prostate Cancer, in it the following recommendations appear:

• After a negative initial biopsy in patients with low probability for harboring GG2+ prostate cancer, clinicians should not reflexively perform biomarker testing
• After a negative biopsy, clinicians may use blood, urine, or tissue-based biomarkers selectively for further risk stratification if results are likely to influence the decision regarding repeat biopsy or otherwise substantively change the patient’s management. (Conditional Recommendation; Evidence Level: Grade C) (Wei, 2023)

Consistent with the Agency for Healthcare Research and Quality’s (AHRQ) evidentiary framework for blood-based cancer screening tests, diagnostic accuracy alone is insufficient to establish clinical net benefit in the absence of evidence demonstrating improved health outcomes and acceptable tradeoffs between benefits and harms (AHRQ, 2024).

The National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guidelines in Oncology for Prostate Cancer Early Detection (2025) state that consideration may be given to biomarkers before biopsy in men with serum PSA levels of > 3 ng/ml who desire more specificity. These tests are also options for men being considered for repeat biopsy after an initial benign result (2B recommendation). NCCN cautions:

Clinicians and patients should be aware that the extent of validation of these tests across diverse populations is variable and mostly limited to retrospective observational studies, often with industry support. There are risks in using biomarker tests that lack robust validation to change management decisions, as they may drive patients or providers to inappropriate options. In particular, these tests may underestimate risk, leading to delayed or missed diagnosis.

The 4Kscore and IsoPSA tests are the only protein biomarker tests that have received premarket approval by the FDA for the screening, detection, and management of prostate cancer. The Centers for Medicare & Medicaid Services (CMS) Local Coverage Determinations (LCDs) L37042, L38985, L38997, L39005 and L39007 titled, Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer, provide a framework for coverage consistent with demonstration of clinical utility.

While the results of industry sponsored studies and systematic reviews (Klein, 2022; Wang, 2020; Zhao, 2020; Zhou, 2023) are promising, they have not demonstrated that the use of protein biomarker testing improves health related outcomes and how the use of biomarker results affects treatment decisions.

Prostate cancer is the most commonly diagnosed cancer, other than skin cancers, in North American men. According to the American Cancer Society (ACS, 2026), estimated new cases and disease-related deaths from prostate cancer in the United States in 2025 is 313,780 and 35,770 respectively. Prostate cancer is the second leading cause of cancer death in American men, exceeded only by lung cancer. Men in the U.S. have about 1 chance in 8 of being diagnosed with this malignancy and about 1 man in 44 will die of the disease. Prostate cancer is more likely to develop in older men, 65 or older, and in non-Hispanic Black men.

At this time, the gold standard for diagnosis of prostate cancer is a prostate biopsy. However, this technique is invasive and poses some risks to the individual. In an attempt to create a reliable, accurate and clinically useful non-invasive alternative to prostate biopsy, researchers have developed blood and urine-based laboratory tests.

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For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Abdallah N, Campbell RA, Benidir T, et al. Low baseline isopsa index is associated with a prolonged low risk of clinically significant prostate cancer diagnosis in men with an elevated PSA. Urology. 2025; 201:69-75.
2. Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J Clin Oncol. 2019; 37(13):1120-1129.
3. Auvinen A, Tammela TLJ, Mirtti T, et al. Prostate cancer screening with PSA, Kallikrein Panel, and MRI: the ProScreen randomized trial. JAMA. 2024; 331(17):1452-1459.
4. Benidir T, Lone Z, Wood A, et al. Using IsoPSA with prostate imaging reporting and data system score may help refine biopsy decision making in patients with elevated PSA. Urology. 2023; 176:115-120.
5. Borque-Fernando Á, Rubio-Briones J, Esteban LM, et al. Role of the 4Kscore test as a predictor of reclassification in prostate cancer active surveillance. Prostate Cancer Prostatic Dis. 2019; 22(1):84-90.
6. Bryant RJ, Sjoberg DD, Vickers AJ, et.al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015; 11:107(7).
7. Carlsson S, Maschino A, Schröder F, et al. Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Eur Urol. 2013; 64(5):693-699.
8. Darst BF, Chou A, Wan P, et al. The four-kallikrein panel is effective in identifying aggressive prostate cancer in a multiethnic population. Cancer Epidemiol Biomarkers Prev. 2020; 29(7):1381-1388.
9. de Almeida S R Jr, Thomas J, Mason MM, et al. Optimum threshold of the 4Kscore for biopsy in men with negative or indeterminate multiparametric magnetic resonance imaging. BJUI Compass. 2023; 4(5):591-596.
10. Hougen HY, Sjoberg DD, Thomas J, et al. Adding a coefficient for race to the 4Kscore improves calibration for Black men. J Urol. 2024; 211(3):392-399.
11. Hyndman ME, Paproski RJ, Kinnaird A, et al. Development of an effective predictive screening tool for prostate cancer using the ClarityDX machine learning platform. NPJ Digit Med. 2024; 7(1):163.
12. Josefsson A, Månsson M, Kohestani K, et al. Performance of 4Kscore as a reflex test to prostate-specific antigen in the GÖTEBORG-2 prostate cancer screening trial. Eur Urol. 2024; 86(3):223-229.
13. Klein EA, Partin A, Lotan Y, et al. Clinical validation of IsoPSA, a single parameter, structure-focused assay for improved detection of prostate cancer: a prospective, multicenter study. Urol Oncol. 2022; 40(9):408.e9-408.e18.
14. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore® test reduces prostate biopsy rates in community and academic urology practices. Rev Urol. 2015; 17(4):231-240.
15. Parekh DJ, Punnen S, Sjoberg DD, et.al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol. 2015; 68(3):464-470.
16. Punnen S, Freedland SJ, Polascik TJ, et al. A multi-institutional prospective trial confirms noninvasive blood test maintains predictive value in African American men. J Urol. 2018; 199(6):1459-1463.
17. Rasmussen M, Fredsøe J, Tin AL, et al. Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence. Br J Cancer. 2022; 126(7):1004-1009.
18. Russo GI, Regis F, Castelli T, et al. A systematic review and meta-analysis of the diagnostic accuracy of prostate health index and 4-kallikrein panel score in predicting overall and high-grade prostate cancer. Clin Genitourin Cancer. 2017; 15(4):429-439.
19. Scovell JM, Hettel D, Abouassaly R, et al. IsoPSA^® reduces provider recommendations for biopsy and magnetic resonance imaging in men with total prostate specific antigen ≥4 ng/ml: a real-world observational clinical utility study. Urol Pract. 2022; 9(2):173-180.
20. Scher HI, Graf RP, Schreiber NA, et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 2018; 4(9):1179-1186.
21. Sharp A, Welti JC, Lambros MBK, et al. Clinical utility of circulating tumour cell androgen receptor splice variant-7 status in metastatic castration-resistant prostate cancer. Eur Urol. 2019; 76(5):676-685.
22. Shore ND, Polikarpov DM, Pieczonka CM, et al. Development and evaluation of the MiCheck^® Prostate test for clinically significant prostate cancer. Urol Oncol. 2023; 41(11):454.e9-454.
23. Sultan MI, Huynh LM, Kamil S, et al. Utility of noninvasive biomarker testing and MRI to predict a prostate cancer diagnosis. Int Urol Nephrol. 2024; 56(2):539-546.
24. Thomas J, Atluri S, Zucker I, et al. A multi-institutional study of 1,111 men with 4K score, multiparametric magnetic resonance imaging, and prostate biopsy. Urol Oncol. 2023; 41(10): 430.e9-430.e16.
25. Verbeek JFM, Bangma CH, Kweldam CF, et al. Reducing unnecessary biopsies while detecting clinically significant prostate cancer including cribriform growth with the ERSPC Rotterdam risk calculator and 4Kscore. Urol Oncol. 2019; 37(2):138-144.
26. Vickers A, Cronin A, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010; 28(15):2493-2498.
27. Vickers A, Hugosson J, Lilja H. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden. BMC Med. 2008; 6:19.
28. Wang B, Benidir T, Dortche K, et al. IsoPSA density improves risk stratification and biopsy decision-making for clinically significant prostate cancer. Urol Oncol. 2026; 44(1):70.e1-70.e9.
29. Wang Z, Shen H, Liang Z, et al. The characteristics of androgen receptor splice variant 7 in the treatment of hormonal sensitive prostate cancer: a systematic review and meta-analysis. Cancer Cell Int. 2020; 20:149.
30. White J, Shenoy BV, Tutrone RF, et al. Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis. 2018; 21(1):78-84.
31. Zhao S, Liao J, Zhang S, et al. The positive relationship between androgen receptor splice variant-7 expression and the risk of castration-resistant prostate cancer: a cumulative analysis. Front Oncol. 2023; 13:1053111.
32. Zhou J, Liu R. The association between androgen receptor splice variant 7 status and prognosis of metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. Andrologia. 2020; 52(7):e13642.

Government Agency, Medical Society, and Other Authoritative Publications:

1. AHRQ. Blood-based tests for multiple cancer screening: a systematic review. 2024. Available at: https://effectivehealthcare.ahrq.gov/sites/default/files/related_files/cell-free-dna-protocol.pdf. Accessed January 13, 2026.
2. American Cancer Society. Key statistics for prostate cancer. 2026. Available at: https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. Accessed on January 07, 2026.
3. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): 4Kscore Test Algorithm. LCD L37798. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=37798&ver=13&keyword=4k%20score&keywordType=starts&areaId=all&docType=NCA,CAL,NCD,MEDCAC,TA,MCD,6,3,5,1,F,P&contractOption=all&sortBy=relevance&bc=1. Accessed on January 9, 2026.
4. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): MolDX: Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer.
   • LCD L37042. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=39042&ver=7&keyword=prostate&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on January 07, 2026.
   • LCD L38985. Available at https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38985&ver=17&keyword=prostate&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on January 07, 2026.
   • LCD L38997. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38997&ver=11&bc=0.  Accessed on January 07, 2026.
   • LCD L39005. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=39005&ver=8&keyword=prostate&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on January 07, 2026.
   • LCD L39007. Available at https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=39007&ver=9&keyword=prostate&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on January 07, 2026.
5. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): MolDX: Prostate Cancer Genomic Classifier Assay for Men with Localized Disease.
   • LCD L38292. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38292&ver=17&bc=0.  Accessed on January 07, 2026.
   • LCD L38303. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38303&ver=12&bc=0.  Accessed on January 07, 2026.
   • LCD L38339. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38339&ver=16&bc=0.  Accessed on January 07, 2026.
   • LCD L38341. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38341&ver=13&bc=0. Accessed on January 07, 2026.
   • LCD L38433. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38433&ver=9&bc=0. Accessed on January 07, 2026.
6. NCCN Clinical Practice Guidelines in Oncology (NCCN ).^© 2026. National Comprehensive Cancer Network. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 07, 2026.
   • Prostate Cancer Early Detection. V1.2026. Revised November 25, 2025.
7. U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health. Summary of safety, effectiveness of Data (SSED): 4Kscore Test. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190022B.pdf. Accessed on January 07, 2026.
8. U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health. Summary of safety, effectiveness of Data (SSED): IsoPSA Assay. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf20/P200048B.pdf. Accessed on January 07, 2026.
9. U. S. Preventive Services Task Force. Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018; 319(18):1901-1913.
10. Wei JT, Barocas D, Carlsson S, et al. Early detection of prostate cancer: AUA/SUO guideline part I: prostate cancer screening. J Urol. 2023; 210(1):45-53.

4Kscore test
AR-V7
ClarityDx Prostate
IsoPSA
MiCheck Prostate
OPKO Diagnostics
PanGIA Prostate

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