FDA OKs Blood-Based Test to Help Detect High-Grade Prostate Tumors

FDA OKs Blood-Based Test to Help Detect High-Grade Prostate Tumors | MedPage Today

FDA Approves New Blood Test to Better Detect Aggressive Prostate Cancer

BLUF (Bottom Line Up Front): The FDA has approved IsoPSA, a novel blood test that analyzes PSA at the molecular level to more accurately identify men with aggressive prostate cancer. In clinical studies, the test demonstrated 90% sensitivity for detecting high-grade tumors while potentially reducing unnecessary biopsies by 55%, offering men with elevated PSA a more precise tool for deciding whether to proceed with biopsy.

Understanding the New Test

Men facing elevated PSA levels now have access to a more sophisticated diagnostic tool following the FDA's December 2025 approval of Cleveland Diagnostics' IsoPSA test. Unlike standard PSA testing, which measures only the total amount of prostate-specific antigen in blood, IsoPSA examines the structural variations (isoforms) of the PSA molecule itself to determine whether elevated levels originate from cancerous or benign prostate tissue.

The test addresses a longstanding challenge in prostate cancer screening: standard PSA testing cannot distinguish between elevated levels caused by cancer versus those caused by benign conditions like prostate enlargement or inflammation. This limitation has led to countless unnecessary biopsies for men without cancer while occasionally missing aggressive disease.

Clinical Performance

The approval draws on substantial clinical evidence, including a prospective multicenter study involving 888 men scheduled for prostate biopsy at 14 U.S. sites. The research demonstrated that IsoPSA achieved an area under the curve of 0.783 for detecting high-grade prostate cancer, with sensitivity reaching 90.2% and specificity of 45.5%. The test's negative predictive value of 89.3% means that men with a negative IsoPSA result have approximately a 90% likelihood of not having high-grade disease.

Perhaps most compelling for patients and physicians making biopsy decisions, a real-world clinical utility study involving 38 healthcare providers and 900 men aged 50 and older with PSA levels of at least 4 ng/mL showed that IsoPSA testing resulted in a 55% net reduction in biopsy recommendations. This suggests the test could help hundreds of thousands of men annually avoid unnecessary invasive procedures while maintaining high detection rates for clinically significant cancer.

The Technology Behind IsoPSA

IsoPSA technology exploits a fundamental characteristic of cancer cells: they produce structurally different versions of PSA compared to normal prostate cells. The test uses an in vitro diagnostic kit to analyze blood samples and identify these molecular signatures. According to Cleveland Diagnostics, this approach provides physicians with actionable information that standard PSA testing cannot deliver.

The company's research suggests that cancer cells alter their protein production machinery in ways that create distinctive PSA variants. By detecting these variants, IsoPSA aims to answer the critical question that has plagued PSA screening since its introduction: does this elevated number represent dangerous cancer or something benign?

Expert Perspectives and Clinical Integration

Dr. Aaron Berger, a urologist with Associated Urological Specialists in Chicago, emphasized the test's potential clinical impact: "IsoPSA represents a meaningful advancement, giving physicians a tool that improves risk assessment and helps us make more informed biopsy decisions with greater confidence." His comments reflect growing recognition among urologists that refinements to PSA testing are essential for improving prostate cancer detection while reducing overdiagnosis and overtreatment.

The test has already gained acceptance within clinical guidelines, having been incorporated into the National Comprehensive Cancer Network's prostate cancer early detection recommendations. Additionally, Medicare provides coverage for eligible beneficiaries, removing a potential access barrier for the demographic most affected by prostate cancer.

Broader Context: The Evolution of PSA Testing

The approval of IsoPSA comes amid ongoing efforts to refine prostate cancer screening and diagnosis. Standard PSA testing, introduced in the late 1980s, revolutionized prostate cancer detection but created significant challenges related to overdiagnosis of indolent disease that might never cause harm during a man's lifetime.

Over the past decade, researchers have developed numerous biomarkers and genetic tests intended to improve upon PSA's limitations. These include the Prostate Health Index (PHI), which measures different forms of PSA; the 4Kscore test, which combines multiple biomarkers with clinical information; SelectMDx, which analyzes gene expression in urine; and tissue-based tests like Decipher and Prolaris used after biopsy or surgery to assess cancer aggressiveness.

IsoPSA joins this expanding toolkit with a distinct approach focused on PSA structural analysis. The test's 90% sensitivity for high-grade disease positions it as potentially useful for identifying men who need biopsy, while its ability to reduce unnecessary procedures addresses the overdiagnosis concern that has complicated PSA screening recommendations.

Implications for Patients

For men confronting elevated PSA results, IsoPSA offers potential advantages in the difficult decision about whether to proceed with prostate biopsy. The test's high negative predictive value means that a negative result provides substantial reassurance that high-grade cancer is unlikely, potentially allowing some men to defer or avoid biopsy while maintaining appropriate surveillance.

However, patients should understand the test's limitations. The 45.5% specificity means that among men without high-grade cancer, roughly half will still receive positive IsoPSA results and might be recommended for biopsy. The positive predictive value of 47.7% indicates that fewer than half of men with positive IsoPSA results will actually have high-grade disease detected on biopsy.

These statistics underscore that IsoPSA, like all diagnostic tests, provides probability information rather than certainty. Clinical judgment incorporating age, family history, digital rectal exam findings, and patient preferences remains essential in biopsy decision-making.

Access and Availability

With FDA approval secured and Medicare coverage established, IsoPSA should become increasingly available through urology practices and medical centers. Cleveland Diagnostics has not publicly disclosed pricing for patients paying out of pocket or specifics of commercial insurance coverage beyond Medicare.

Men interested in IsoPSA testing should discuss the option with their urologist or primary care physician, particularly if facing borderline PSA elevations where biopsy benefits and risks are closely balanced. The test is indicated for men aged 50 and older with elevated PSA, though specific PSA thresholds for testing may vary by clinical practice.

Future Directions

The approval of IsoPSA reflects broader momentum toward precision medicine in prostate cancer, with diagnostic decisions increasingly guided by molecular information rather than clinical parameters alone. Ongoing research continues to explore additional biomarkers, imaging techniques like PSMA PET scans, and artificial intelligence applications that may further refine early detection strategies.

For the prostate cancer community, IsoPSA represents another step toward the long-sought goal of detecting dangerous cancers early while avoiding unnecessary treatment of indolent disease. As with any new diagnostic tool, real-world experience will be essential in determining how IsoPSA performs across diverse patient populations and practice settings.

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Sources

1. Bassett, M. (2025, December 1). FDA OKs Blood-Based Test to Help Detect High-Grade Prostate Tumors. MedPage Today. https://www.medpagetoday.com/hematologyoncology/prostatecancer/113474

2. Cleveland Diagnostics. (2024). IsoPSA Test: Prostate Cancer Detection. https://www.clevelanddiagnostics.com/isopsa

3. Xiong, Y., et al. (2023). Clinical validation of a novel blood-based prostate-specific antigen isoform test for detection of high-grade prostate cancer. The Journal of Urology, 209(4), 693-701. https://www.auajournals.org/doi/10.1097/JU.0000000000003162

4. Saini, S., et al. (2024). Real-world clinical utility of PSA glycosylation testing in prostate biopsy decision-making: A multi-provider observational study. Urologic Oncology: Seminars and Original Investigations, 42(6), 241-248.

5. National Comprehensive Cancer Network. (2025). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection, Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf

6. U.S. Food and Drug Administration. (2025, November). 510(k) Premarket Notification: IsoPSA Test System (K233849). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K233849

7. Centers for Medicare & Medicaid Services. (2024). Medicare Coverage Database: IsoPSA Test (LCD L39284). https://www.cms.gov/medicare-coverage-database/

8. Loeb, S., & Catalona, W. J. (2024). The Prostate Health Index: A new biomarker for prostate cancer detection. European Urology Focus, 10(1), 15-22.

 

Sidebar: Current Evidence IsoPSA for Active Surveillance and Biochemical Recurrence

BLUF: While IsoPSA shows promise for active surveillance monitoring based on its ability to maintain stable risk stratification over 30 months, it is not currently FDA-approved for either active surveillance or biochemical recurrence detection. The test's current FDA approval is limited to helping determine initial biopsy decisions in men aged 50+ with elevated PSA.

Active Surveillance Potential

Recent data demonstrates that IsoPSA maintains reliable risk stratification over 30 months, with low-risk patients remaining stable during that period. This stability suggests potential utility for active surveillance, but important limitations exist:

Current Status: According to Cleveland Clinic urologic oncologist Dr. Zeyad Schwen, IsoPSA is primarily valuable in the screening and initial diagnosis setting and has not yet been studied in the active surveillance population.

Potential Applications Being Explored: Researchers are investigating whether IsoPSA can be used in active surveillance populations, given its ability to predict Gleason 7 or higher disease. The test's performance characteristics suggest it could theoretically help monitor disease progression, as changes in IsoPSA scores might indicate disease progression requiring active treatment, though this requires further study.

Practical Monitoring Value: For patients with low IsoPSA scores (less than 6), their risk over 30 months for clinically significant prostate cancer is approximately 5%, which could influence monitoring frequency and intensity.

Biochemical Recurrence Detection

The search results reveal no published evidence that IsoPSA has been studied or validated for detecting biochemical recurrence after radical prostatectomy or radiation therapy. This represents a significant gap, as biochemical recurrence monitoring relies on different biological mechanisms than initial cancer detection.

Why IsoPSA May Not Apply to Recurrence:

1. Different Disease States: Biochemical recurrence after treatment represents a fundamentally different clinical scenario than pre-biopsy risk assessment. After prostatectomy, PSA should be undetectable, and after radiation, PSA typically drops to a low nadir. IsoPSA's technology analyzes PSA isoform patterns in the context of an intact prostate with either cancer or benign disease.

2. Limited Prostate Tissue: Following radical prostatectomy, there is no prostate gland to produce PSA isoforms. Any detectable PSA comes from residual cancer cells, which may not produce the same isoform patterns that IsoPSA was designed to detect.

3. Established Markers Exist: The extensive literature on biochemical recurrence focuses on PSA kinetics (PSA doubling time, PSA velocity), genomic tests on original tumor tissue (Decipher, Prolaris), and advanced imaging (PSMA PET) rather than serum biomarker analysis.

Comparison with Other Biomarkers in Surveillance

The scientific literature identifies several biomarkers with more established roles in active surveillance:

Blood-based tests with AS data:

• Prostate Health Index (PHI) and 4Kscore have demonstrated improved prediction of clinically significant prostate cancer
• The 4K panel has been studied for predicting high-grade disease in men already diagnosed with Gleason 6 cancer on active surveillance

Tissue-based tests: Oncotype DX Genomic Prostate Score (GPS), Prolaris Cell Cycle Progression score, GenomeDx Decipher score, and ProMark have been evaluated alongside routine clinical indicators, though prospective long-term outcomes in active surveillance populations have not been established.

Urine-based markers: PCA3 and TMPRSS2:ERG gene fusion have been studied in active surveillance cohorts, with PCA3 showing associations with subsequent biopsy reclassification.

Clinical Implications for Patients

For men currently in active surveillance or facing biochemical recurrence, here's what you should know:

Active Surveillance Patients:

• IsoPSA is not yet a standard tool for AS monitoring
• Current AS protocols rely on PSA kinetics, serial biopsies, MRI, and in some cases genomic tests on biopsy tissue
• If you had an IsoPSA test before starting AS, the longitudinal data suggests a low score may provide reassurance, but this shouldn't replace standard AS protocols

Biochemical Recurrence Patients:

• IsoPSA has no established role in BCR management
• Standard approaches focus on PSA doubling time, PSMA PET imaging, and genomic classifiers
• Risk stratification after BCR depends on factors like original Gleason score, PSA kinetics, surgical margins, and interval to recurrence

Research Directions

The 30-month stability data is promising for eventual AS applications, but several research questions remain:

1. Validation in AS cohorts: Prospective studies comparing IsoPSA changes with biopsy reclassification outcomes
2. Integration with MRI: Understanding how IsoPSA performs alongside mpMRI in surveillance protocols
3. Frequency of testing: Determining optimal intervals for repeat IsoPSA during AS
4. Treatment triggers: Establishing IsoPSA thresholds that warrant intervention

Bottom Line

While IsoPSA shows intriguing potential for active surveillance based on its demonstrated stability over time, it remains an investigational application not covered by the current FDA approval. The test has no validated role in detecting or monitoring biochemical recurrence after treatment. Men interested in using IsoPSA for these purposes should understand that they would be participating in what amounts to unvalidated, off-label use of the test.

For active surveillance, established protocols using PSA kinetics, serial biopsies (which can now be reduced with MRI guidance), and in selected cases genomic testing, remain the standard of care. For biochemical recurrence, PSA doubling time, PSMA PET imaging, and risk stratification tools validated specifically for the post-treatment setting provide more appropriate guidance for management decisions.

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Sources

1. Targeted Oncology. (2025, December 1). Long-Term Data Validates IsoPSA for Prostate Cancer Risk Stratification. https://www.targetedonc.com/view/long-term-data-validates-isopsa-for-prostate-cancer-risk-stratification

2. Urology Times. (2025, December 1). The potential role for IsoPSA in prostate cancer risk assessment. https://www.urologytimes.com/view/the-potential-role-for-isopsa-in-prostate-cancer-risk-assessment

3. Faiena, I., et al. (2018). Biomarker in Active Surveillance for Prostate Cancer: A Systematic Review. Frontiers in Oncology, 8, 352. https://pmc.ncbi.nlm.nih.gov/articles/PMC8428218/

4. Cleveland Clinic. (2024). The Art of Active Surveillance for Prostate Cancer [Podcast]. Cancer Advances. https://my.clevelandclinic.org/podcasts/cancer-advances/the-art-of-active-surveillance-for-prostate-cancer

5. Sotomayor, P.C., et al. (2022). Active Surveillance in Prostate Cancer: Current and Potentially Emerging Biomarkers for Patient Selection Criteria. Urologia Internationalis, 106(12), 1201-1213. https://karger.com/uin/article/106/12/1201/827205

6. Loeb, S., & Tosoian, J.J. (2018). Biomarkers in active surveillance. Translational Andrology and Urology, 7(Suppl 1), S3-S10. https://pmc.ncbi.nlm.nih.gov/articles/PMC5861276/

7. Klotz, L., et al. (2021). Active surveillance for prostate cancer. Translational Andrology and Urology, 10(6), 2809-2822. https://pmc.ncbi.nlm.nih.gov/articles/PMC8261451/

8. Shore, N.D., et al. (2024). Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification. Prostate Cancer and Prostatic Diseases, 27, 192-201. https://www.nature.com/articles/s41391-023-00712-z

9. Daily News ASCO. Guiding Treatment for Patients With Prostate Cancer With Biochemical Recurrence After Prostatectomy. https://dailynews.ascopubs.org/do/guiding-treatment-patients-prostate-cancer-biochemical-recurrence-after-prostatectomy