PSA Levels Alone May Not Reflect Prostate Cancer Progression

KEY FINDINGS

• In a post-hoc analysis of the ARCHES and PROSPER phase III trials covering 2,551 patients, approximately 25% of patients receiving enzalutamide showed disease progression on imaging (radiographic progression) without any rise in PSA. In some cases, cancer progression was detected by imaging even though the PSA level was undetectable.
• Patients with radiographic progression had worse overall survival regardless of any change in PSA.
• Most patients experienced disease progression while feeling well and reporting no new symptoms.
• The investigators recommend periodic imaging in addition to routine PSA monitoring in patients taking potent androgen receptor inhibitors, particularly during the first two years of treatment.

Study Design and Background

The study, first-authored by Dr. Andrew J. Armstrong of the Duke Cancer Institute with Dr. Cora N. Sternberg of Weill Cornell Medicine as senior author, was published in the Journal of Clinical Oncology. The research is based on a post-hoc analysis of two international, multicentre phase III trials (ARCHES and PROSPER) that evaluated the efficacy of enzalutamide in slowing tumour growth in advanced prostate cancer.

The ARCHES trial enrolled patients with metastatic hormone-sensitive prostate cancer (mHSPC) still responding to hormone therapy, while the PROSPER trial enrolled patients resistant to hormone therapy but without metastases on conventional imaging (nmCRPC). In both trials, patients received either enzalutamide in addition to androgen deprivation therapy (ADT) or placebo/ADT alone; the relationship between radiographic progression (rPD) and PSA changes was examined comparatively.

Key Results

In both trials, patients with progression on imaging - whether or not PSA rose - had significantly shorter overall survival.

The investigators suggest that this finding reflects the fact that some tumours develop growth mechanisms independent of androgen receptor signalling, and that these cells can continue to spread while producing very little PSA. This process, referred to in the literature as "lineage plasticity" or neuroendocrine transformation, is described as an area requiring further research.

"Waiting for a PSA rise may miss cancer growth or spread in some patients receiving modern targeted therapy. This is a finding with the potential to change clinical practice."
- Dr. Cora N. Sternberg, Clinical Director, Englander Institute for Precision Medicine, Weill Cornell Medicine

Implications for Clinical Practice

These findings once again demonstrate that PSA alone is not a sufficient monitoring parameter in day-to-day uro-oncology practice. Particularly in patients with metastatic hormone-sensitive and non-metastatic castration-resistant prostate cancer treated with potent androgen receptor inhibitors (such as enzalutamide, apalutamide and darolutamide), scheduling imaging at defined intervals (CT, bone scintigraphy and, in suitable cases, PSMA PET/CT) emerges as a rational approach even when PSA remains stable.

This approach serves as a caution against the tendency to relax follow-up intervals on the reassurance that "my PSA is fine and I feel well." In clinical decision-making, regularly evaluating imaging findings alongside PSA kinetics is important for detecting disease progression early and revising treatment strategy in a timely manner. The authors also emphasise that the way clinical guidelines treat a PSA rise as the defining element of disease progression needs to be reconsidered.

Conclusion

This new analysis of the ARCHES and PROSPER trials provides strong evidence that PSA remains important in the follow-up of advanced prostate cancer but is not sufficient on its own. Particularly in patients receiving androgen receptor-targeted therapy, not neglecting periodic imaging even when PSA is stable is critically important for the timely detection of silent progression that may affect survival. These data provide a strong rationale for future clinical guidelines to reshape their surveillance protocols.

References

• Armstrong AJ, et al. Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide. Journal of Clinical Oncology, 2026. ascopubs.org/doi/10.1200/JCO-24-02829
• Weill Cornell Medicine Newsroom "PSA Levels Alone May Not Reflect Prostate Cancer Growth" (1 July 2026). news.weill.cornell.edu
• Cornell Chronicle - "PSA levels alone may not reflect prostate cancer growth" (July 2026). news.cornell.edu
• The ASCO Post "Advanced Prostate Cancer: Radiographic Progression and PSA Increase in Patients Treated With Enzalutamide" (10 April 2026). ascopost.com
• EurekAlert! "PSA levels alone may not reflect prostate cancer growth". eurekalert.org