Doctors may be missing prostate cancer growth in some patients by relying solely on PSA (prostate-specific antigen) blood tests, according to new research from Weill Cornell Medicine and Duke University. A comprehensive analysis of over 2,500 men in clinical trials found that roughly one in four patients experienced cancer progression detected on imaging scans even when their PSA levels remained stable or undetectable, and these patients had worse outcomes.

Why Are PSA Levels Becoming Unreliable?

Prostate-specific antigen has been the gold standard for tracking prostate cancer for decades. Doctors routinely measure PSA levels in the blood to monitor whether cancer is progressing or responding to treatment. However, the new findings challenge this long-standing practice, particularly for patients receiving modern targeted therapies like enzalutamide, a drug that blocks androgen receptor signaling, which prostate cancer cells use to grow.

Researchers suspect that some tumors develop resistance mechanisms that allow them to grow independently of androgen receptor signals. In these cases, cancer cells may produce little or no PSA while continuing to spread to other parts of the body. This process, sometimes called lineage plasticity or neuroendocrine transformation, requires further investigation to fully understand.

"We did not expect to see these rates of radiographic progression with low PSA and sometimes even zero PSA. This is a practice-changing paper suggesting that waiting for PSA to increase could delay detection of clinically meaningful disease growth and worse outcomes for patients," said Dr. Cora N. Sternberg, professor of medicine in hematology and medical oncology at Weill Cornell.

Dr. Cora N. Sternberg, Professor of Medicine in Hematology and Medical Oncology at Weill Cornell Medicine

What Did the Research Actually Show?

The study analyzed data from two major clinical trials, ARCHES and PROSPER, which tested enzalutamide in patients with advanced prostate cancer. The ARCHES trial included men whose cancer had spread to other organs but still responded to hormone therapy. The PROSPER trial enrolled patients whose cancer no longer responded to hormone therapy but had not yet spread based on conventional imaging.

In both groups, researchers found similar troubling patterns. Up to 25% of patients receiving enzalutamide showed cancer progression on imaging scans, such as X-rays, CT scans, or bone scans, despite having stable, low, or minimally changing PSA levels. Notably, patients whose cancer progressed on imaging had worse overall survival than those whose cancer had not progressed, regardless of whether their PSA levels changed. Even more concerning, many patients felt well and experienced no new symptoms despite their cancer advancing.

How Should Doctors Monitor Advanced Prostate Cancer Now?

• Periodic Imaging Scans: Researchers recommend that patients receiving potent androgen receptor inhibitors like enzalutamide should undergo periodic imaging scans in addition to routine PSA monitoring, particularly during the first two years of treatment.
• Reassess PSA Guidelines: The investigators suggest that future clinical guidelines should reconsider how PSA increases are used to define cancer advancement and provide clearer recommendations for how often imaging should be performed.
• Monitor for Symptom Changes: Since patients may feel well despite cancer progression, doctors should remain vigilant for any new symptoms or changes in a patient's condition, even when PSA levels appear stable.

The findings represent a significant shift in how doctors should approach monitoring advanced prostate cancer. For years, PSA testing has been the primary tool for tracking disease progression, but this research demonstrates that the relationship between PSA levels and actual tumor growth can become disconnected in some patients, particularly those receiving modern targeted therapies.

"PSA has long been one of the most important tools for tracking prostate cancer, but these results show that waiting for PSA levels to rise may miss cancer growth or spread in some patients receiving modern targeted therapies," explained Dr. Cora N. Sternberg.

Dr. Cora N. Sternberg, Professor of Medicine in Hematology and Medical Oncology at Weill Cornell Medicine

The research was published in the Journal of Clinical Oncology and involved collaboration between Weill Cornell Medicine and Duke University Cancer Institute. Dr. Andrew Armstrong, professor of medicine at Duke Cancer Institute Center for Prostate and Urologic Cancer, led the analysis. The study's implications extend beyond the specific drug tested, as the researchers found similar patterns across different patient populations with advanced prostate cancer, suggesting this may be a broad issue affecting how doctors monitor the disease.

For patients currently undergoing treatment for advanced prostate cancer, these findings underscore the importance of discussing monitoring strategies with their oncologists. While PSA testing remains a valuable tool, it should not be the only measure used to assess whether cancer is progressing. Patients and doctors should work together to determine whether periodic imaging scans are appropriate, especially during the critical early years of treatment when detecting progression early can significantly impact outcomes.