For many patients with prostate cancer, prostate-specific antigen (PSA) is one of the most closely watched numbers in their medical record. A declining PSA can offer reassurance that treatment is working. A rising PSA may prompt concern about disease progression.

Over time, these results often become an important part of how patients and clinicians understand the course of treatment. But what happens when the numbers appear reassuring while the cancer continues to progress?

A 2026 study suggests that this disconnect is an important consideration among patients receiving enzalutamide for advanced prostate cancer. The findings raise questions about how disease progression is monitored and why PSA results should not always be interpreted in isolation.

Examining the Relationship Between PSA and Disease Progression
Researchers conducted a post hoc analysis of two phase 3 clinical trials: ARCHES and PROSPER. Together, the trials included 2551 patients across two distinct prostate cancer populations; ARCHES evaluated enzalutamide plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer, while PROSPER evaluated enzalutamide plus ADT in nonmetastatic castration-resistant prostate cancer.

The investigators examined how frequently radiographic progression occurred without a corresponding PSA increase or without meeting established criteria for PSA progression. Radiographic progression refers to disease worsening detected through imaging, such as the development of new metastatic lesions or growth of existing disease.

The analysis revealed an important disconnect between laboratory findings and imaging results.

Progression Without a PSA Warning
Among 79 patients receiving enzalutamide plus ADT in ARCHES who experienced radiographic progression, 25.3% had no PSA rise at the time progression was identified. Even more notably, 62.0% had not met formal PSA progression criteria.

In PROSPER, among 187 patients receiving enzalutamide plus ADT who experienced radiographic progression, 21.9% had no PSA rise, while 51.3% had not met PSA progression criteria.

These findings suggest that a substantial proportion of patients who develop radiographic progression may do so without the PSA changes that clinicians traditionally associate with worsening disease.

An important distinction is that these percentages describe patients who experienced radiographic progression, not the entire population receiving treatment.

Across all enzalutamide-treated patients in ARCHES, 3.5% experienced radiographic progression without a PSA rise. In PROSPER, the corresponding proportion was 4.4%.

Understanding this difference is essential to interpreting the findings accurately.

Why the Disconnect Matters
PSA remains a valuable biomarker in prostate cancer management, but it does not capture every aspect of disease activity.

Some tumors may progress despite continued suppression of PSA production. Changes in tumor biology, treatment resistance, or disease characteristics may contribute to differences between PSA behavior and radiographic findings.

The investigators also observed a higher frequency of liver metastases among enzalutamide-treated patients with radiographic progression compared with control patients, although the number of events was small.

Importantly, patients who experienced radiographic progression had worse overall survival than those without progression, regardless of whether a PSA increase accompanied the imaging findings.

This reinforces the clinical significance of detecting progression that may not be apparent through PSA monitoring alone.

Implications for Multidisciplinary Monitoring
The findings have practical relevance for clinicians and other members of the cancer care team.

For oncologists, they support considering imaging alongside PSA trends and other clinical indicators when monitoring disease progression. The study does not establish a specific imaging schedule for every patient. Surveillance decisions should continue to reflect disease setting, treatment history, symptoms, and applicable clinical guidelines.

For nurses and navigators, the findings reinforce the importance of paying attention to changes that may not be reflected in laboratory results. New or worsening pain, unexplained fatigue, changes in mobility, or other concerning symptoms may warrant further assessment even when PSA remains stable.

Pharmacists can also contribute by identifying changes in treatment tolerability, medication use, or symptom management that may prompt additional clinical evaluation.

Patient education is another important consideration. Although a stable PSA can be encouraging, patients should understand that it is one component of disease monitoring rather than a definitive measure of treatment success.

Looking at the Complete Clinical Picture
As prostate cancer treatments become more effective at suppressing androgen signaling and controlling PSA, traditional monitoring approaches may need to be considered alongside other indicators of disease activity.

This analysis does not diminish the value of PSA testing. Instead, it clarifies its limitations. Because the research was a post hoc analysis, the findings should be interpreted cautiously and do not independently establish new surveillance guidelines.

Nevertheless, the results offer a clinically relevant message: Effective monitoring requires attention to laboratory values, imaging findings, symptoms, and the patient’s overall condition.

For multidisciplinary oncology teams, the goal is not simply to follow the numbers. It is to recognize when those numbers may not be telling the complete story.

Source
Armstrong AJ, Azad AA, Iguchi T, et al. Radiographic progression with and without prostate-specific antigen rise in patients with advanced prostate cancer treated with enzalutamide. J Clin Oncol. 2026;44:1309-1322.