More than 330,000 men are diagnosed with prostate cancer each year in the U.S., making it the second most common cancer in men.¹ Prostate-specific antigen (PSA) remains a foundational tool in prostate cancer screening and risk assessment. It is widely available, familiar to clinicians and laboratories, and valuable for identifying patients who may warrant further evaluation. But an elevated PSA concentration does not, on its own, establish whether a patient has prostate cancer or whether a detected cancer is likely to be clinically significant.

PSA levels can rise for reasons other than malignancy, including benign prostatic hyperplasia (BPH), inflammation, infection, even a recent bike ride, and more. The critical question after an elevated result, therefore, is not simply whether PSA is high. It is how clinicians can use the available information to determine the most appropriate next step for that individual patient.

The evolving screening pathway increasingly works to answer that question through a layered risk assessment, using PSA as an entry point and incorporating additional approaches, biomarkers, imaging, clinical history, and tissue biopsy when appropriate. This approach aims to better identify patients who may harbor clinically significant disease while avoiding unnecessary invasive procedures for those at lower risk. Current American Urological Association (AUA)/Society of Urologic Oncology (SUO) guidance supports use of adjunctive blood or urine markers when the result would influence the decision to proceed with biopsy, and it recognizes a role for MRI before an initial biopsy in appropriate patients.² 

Looking beyond concentration

Traditional PSA testing measures the amount of PSA circulating in the blood. That concentration remains clinically meaningful, but it may not fully distinguish PSA associated with malignant prostate tissue from PSA originating in benign processes. As a result, newer approaches seek to extract more biologically specific information from PSA itself. One such approach examines structural changes or variants of the PSA protein that may be associated with cancer-related biology. Rather than just asking how much PSA is present, structural analysis asks whether the PSA detected has characteristics that may help differentiate benign from malignant tissue.

This distinction is important because an elevated PSA is common and often nonspecific, resulting in important practical consequences. The National Cancer Institute estimates that only about 25% of men who undergo prostate biopsy because of an elevated PSA are found to have prostate cancer, meaning many patients undergo further testing and invasive procedures for a result ultimately unrelated to malignancy. It is also estimated that 6%-7% of men receive a false-positive PSA result during any given screening round, underscoring the need for tools that help refine risk before an invasive diagnostic procedure is considered.³ 

Better risk stratification before biopsy

The historical pathway from elevated PSA directly to biopsy is giving way to a more nuanced model. A repeat PSA test may first be appropriate to confirm a newly elevated result. From there, clinicians can integrate factors such as age, family history, race, secondary biomarker results, structural protein analysis, and imaging findings to better estimate the risk of clinically significant cancer.

Secondary biomarker testing can be particularly useful when a result may change management of the diagnostic process. The objective is to use biomarkers selectively in patients for whom uncertainty remains after initial assessment. A more informative risk estimate can support a more confident decision to monitor, obtain imaging, and refer to urology for consideration of biopsy.

Blood-based tests that evaluate structural variants of PSA offer an example of this evolving approach. IsoPSA, for instance, assesses cancer-specific structural variants of the PSA protein rather than PSA concentration alone and is intended to be used alongside other patient information when considering whether biopsy is appropriate. Used in the proper clinical context, this type of testing can contribute to a more individualized diagnostic pathway.⁴

Biomarkers, imaging, and biopsy work together

No single test replaces the full diagnostic evaluation for prostate cancer. Instead, biomarkers, imaging, and biopsy provide complementary information that can help clinicians move from an initial signal of risk toward a more confident diagnosis. Biomarker testing may help refine the likelihood that a patient has clinically significant disease, while imaging can provide information about the prostate’s anatomy and identify areas that may warrant closer evaluation. These findings can be interpreted alongside the patient’s age, family history, physical examination, PSA history, and other clinical factors.

When the combined assessment indicates a meaningful likelihood of clinically significant cancer, tissue biopsy remains necessary to establish a diagnosis and more fully characterize the disease. Biomarker results can help identify patients who may benefit from further evaluation, while imaging can identify and localize areas of the prostate that appear suspicious. That anatomical information can then help guide targeted tissue sampling from those areas, alongside other biopsy approaches (e.g., systematic biopsy) as clinically appropriate.

The goal is not to substitute one test for another. It is to use each source of information at the appropriate point in the diagnostic pathway, helping clinicians select the next step that best reflects the individual patient. A more integrated approach may reduce unnecessary procedures while supporting timely diagnosis when biopsy is warranted.

The laboratory’s evolving role

As testing moves from a single-marker screening model to more precise, clinically actionable risk assessments, laboratories are central to this transition. As assays become more sophisticated, laboratory professionals must evaluate not only analytical performance but also how a test fits into real-world workflows and clinical decision making.

For a biomarker assay to be useful in routine care, it must provide reliable, interpretable results and have a clear role in the care pathway. Laboratory teams can help support appropriate utilization by understanding an assay’s intended-use population, specimen and handling requirements, analytical characteristics, turnaround time, reporting format, and limitations. Collaboration among laboratorians, pathologists, primary care clinicians, advanced practice providers, and urologists is essential to ensuring that results are applied to the right patient population and at the right decision point.

The future of prostate cancer early detection is not about abandoning PSA. It is about using PSA as the starting point for a more informed diagnostic process, then adding more specific biomarker information, imaging, and patient-level clinical factors to guide what happens next. For laboratories, this evolution represents an opportunity to provide information that is not only analytically sound, but also more meaningful for patient care.

References

1. Key statistics for prostate cancer. American Cancer Society. Updated January 13, 2026. Accessed September 24, 2026. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html. 
2. Wei JT, Barocas D, Carlsson S, et al. Early detection of prostate cancer: AUA/SUO guideline part II: Considerations for a prostate biopsy. J Urol. 2023;210(1):54-63. doi:10.1097/JU.0000000000003492.
3. Grubb RL 3rd, Pinsky PF, Greenlee RT, et al. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int. 2008;102(11):1524-30. doi:10.1111/j.1464-410X.2008.08214.x. 
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. doi:10.1016/j.urology.2023.03.014.