FDA Approves Novel Blood-Based Prostate Cancer Test for Elevated PSA Levels

The FDA has approved IsoPSA® in vitro diagnostic kit as an aid in the decision for prostate biopsy for male patients 50 years or older who have elevated prostate-specific antigen (PSA) levels, according to a press release from the developer, Cleveland Diagnostics.¹ The approval occurred through the Premarket Approval process.

Notably, IsoPSA in vitro diagnostics kit utilizes the IsoClear™ platform and investigates protein biomarkers at a structural level in the blood to identify relevant insights into one’s disease state. Additionally, IsoPSA is included in clinical practice guidelines such as the 2025 NCCN Prostate Cancer Early Detection Guideline and the 2023 Early Detection of Prostate Cancer: American Urology Association/Society of Urologic Oncology Guideline.

Clinical evidence from a large-scale, prospective study, which evaluated the diagnostic performance of IsoPSA for identifying high-grade and any-grade prostate cancer risk in men 50 years or older with a total PSA greater than or equal to 4 ng/ml, as well as data from supporting analytical validation studies, supported the FDA’s decision.²

In the prospective, multicenter study, the overall disease prevalence was 35.6% for high-grade prostate cancer and 58.9% for any prostate cancer. The absolute values for IsoPSA index demonstrated increases from benign to low-grade prostate cancer to high-grade prostate cancer.

Reportedly, IsoPSA outperformed total PSA and percentage of free PSA for both histopathological outcomes, as measured by area under the curve (AUC). For high-grade prostate cancer risk, the AUC was 0.783 (95% CI, 0.752-0.814) with IsoPSA compared with 0.672 (95% CI, 0.639-0.706) with total PSA and 0.724 (95% CI, 0.690—0.758) with percentage free PSA (P <.001). An overall accuracy advantage when the total PSA was 4 to 10 ng/ml was also observed with IsoPSA vs percentage free PSA.

For high-grade prostate cancer, IsoPSA demonstrated a sensitivity and specificity of 0.902 and 0.455, respectively, with a positive predictive value (PPV) and negative predictive value (NPV) of 0.477 and 0.893, respectively. With total PSA, the sensitivity and specificity were 0.931 and 0.202, and the PPV and NPV were 0.361 and 0.858; with percentage free PSA, the sensitivity and specificity were 0.947 and 0.137, and the PPV and NPV were 0.382 and 0.820.

For any-grade prostate cancer, with IsoPSA, the sensitivity and specificity were 0.887 and 0.416, respectively, with a PPV and NPV of 0.685 and 0.720. With total PSA, the sensitivity and specificity were 0.883 and 0.214, and the PPV and NPV were 0.599 and 0.580, respectively. With percentage free PSA, the sensitivity and specificity were 0.927 and 0.156, respectively, with a PPV and NPV of 0.621 and 0.590.

Additionally, the selected IsoPSA index cutoffs indicated that an estimated 46% of high-grade and 42% of any-grade biopsies could be avoided in low-risk patients. IsoPSA also maintained accuracy in clinically relevant subgroups.

“FDA approval of our IsoPSA kit marks a significant milestone in Cleveland Diagnostics’ mission to help physicians and patients detect cancer early when it is most treatable and survivable,” stated Arnon Chait, PhD, president and chief executive officer of Cleveland Diagnostics, in the press release.¹ “We remain focused on executing our commercial strategy and expanding access to IsoPSA, to the benefit of patients nationwide.”

The study enrolled 1839 male patients who were scheduled for prostate biopsy at 8 academic and community sites between August 2015 and August 2020. Of these patients, 205 and 888 were evaluable in the prevalidation and validation phases, respectively. It was noted that for total PSA and free PSA, the evaluable prevalidation and validation groups included patients who were excluded from the evaluation of IsoPSA due to analytical factors.

IsoPSA was administered in 2 steps. In the first, the IsoPSA Reagent, comprising a customized aqueous 2-phase physicochemical system, was utilized to partition PSA structural variants based on differences in molecular structure and protein-protein interactions from plasma samples collected per protocol.The second step required using FDA-approved total and free PSA immunoassays to measure total and free PSA in the native plasma samples and the IsoPSA Reagent top-phase fraction.

The trial was set up in 2 defined steps, which were the prevalidation and validation steps. In the prevalidation step, the objective was to establish IsoPSA index cutoff values for high-grade prostate cancer and any-grade prostate cancer with a sensitivity of 90% or more by receiver operating characteristic (ROC) analysis. In the validation step, the objectives were to validate IsoPSA index cutoff values in the prevalidation step and estimate the overall diagnostic performance characteristics of IsoPSA using ROC analysis, compare the accuracy of IsoPSA to total PSA and percentage free PSA, and evaluate IsoPSA in clinically relevant subgroups.

“FDA approval underscores the value and clinical utility of IsoPSA in distinguishing benign elevations of PSA from those due to high-grade cancer,” said Eric A. Klein, MD, Emeritus chair of the Glickman Urological and Kidney Institute at Cleveland Clinic, and distinguished scientist at GRAIL, Inc, in the press release.¹ “I’m very pleased to see this milestone achieved; it represents the culmination of extensive study and test development over the past decade.”

References

1. FDA approves IsoPSA® -- Cleveland Diagnostics’ novel blood-based prostate cancer test. News release. Cleveland Diagnostics. December 1, 2025. Accessed December 1, 2025. https://tinyurl.com/2wda4xmy
2. 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. doi:10.1016/j.urolonc.2022.06.002