Patients with advanced prostate cancer may need regular imaging scans to detect tumor growth even if their prostate-specific antigen (PSA) levels are stable, according to an analysis led by researchers at Weill Cornell Medical College and Duke University. Prostate-specific antigen (PSA) is a protein in the blood that doctors regularly monitor for cancer progression. In some cases, scans may detect cancer progression even if the PSA level is undetectable.
This recent study, published in the Journal of Clinical Oncology, analyzed data from more than 2,500 men who participated in two multinational phase 3 clinical trials testing enzalutamide to slow or stop tumor growth in patients with advanced prostate cancer. This drug targets the androgen receptor, a protein that prostate cancer cells use to receive growth signals from male hormones such as testosterone. The trials (ARCCHES and PROSPER) evaluated the spread or growth of cancer with imaging scans, along with changes in PSA levels during treatment. Researchers looked at cases of radiographic progression, meaning cancer growth or spread detected by imaging tests such as X-rays, CT scans, or bone scans.
In up to about 25% of patients, X-rays show that prostate cancer has progressed without a rise in PSA levels, leading to a worse outcome. PSA has long been one of the most important tools for tracking prostate cancer, but the results show that waiting for PSA levels to rise may cause cancer to grow or spread in some patients receiving the latest targeted therapies. ”
Dr. Cora N. Sternberg, senior author, Weill Cornell Professor of Hematology and Medical Oncology, and medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center
Dr. Andrew Armstrong, professor of medicine at the Prostate and Urinary Cancer Center at Duke Cancer Institute at Duke University, is the paper’s lead author.
Clinical trial data suggests quiet growth
The ARCHES trial enrolled patients whose prostate cancer had spread but still responded to hormone therapy that lowered testosterone levels or inhibited the cancer’s ability to use testosterone signals to grow. Among these patients receiving enzalutamide, some experienced cancer progression on imaging studies even though their PSA levels were stable, low, or barely changing.
Researchers found similar results in the PROSPER trial, which enrolled patients with non-metastatic castration-resistant prostate cancer. This meant that, based on conventional imaging, the prostate cancer was no longer responsive to hormone therapy, but the cancer had not spread to other organs.
Patients taking enzalutamide whose cancer was progressing on imaging tests had shorter overall survival than those whose cancer was not progressing, regardless of change in PSA. The study also found that patients often did well, with no new symptoms, even though their cancer was advanced. Because the findings in both groups were similar, this may be a widespread problem across advanced prostate cancer.
To understand this phenomenon, researchers looked for clues as to why PSA and cancer progression were not linked. They suspect that some tumors may have evolved resistance mechanisms that allow them to grow independently of androgen receptor signaling. These cancer cells may produce little or no PSA while they continue to spread. This process, sometimes referred to as lineage plasticity or neuroendocrine change, requires continued study.
More accurate patient monitoring
Based on the results, the researchers suggest that patients receiving strong androgen receptor blockers, such as enzalutamide, may benefit from regular imaging in addition to regular PSA monitoring, especially during the first two years of treatment. They suggest that future clinical guidelines should reconsider how increasing PSA defines cancer progression and provide clearer recommendations about the frequency of imaging tests.
“We didn’t expect to see this rate of progression on X-rays even with low PSA, and in some cases zero PSA,” said Dr. Sternberg, who is also a member of the Sandra Edward Meyer Cancer Center. “This is a practice-changing paper suggesting that waiting for PSA to rise may delay detection of clinically meaningful disease growth and worsen patient outcomes.”
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Reference magazines:
Armstrong, A.J. others. (2026). Radiographic progression according to the presence or absence of prostate-specific antigen elevation in patients with advanced prostate cancer treated with enzalutamide. Journal of Clinical Oncology. DOI: 10.1200/jco-24-02829. https://ascopubs.org/doi/10.1200/JCO-24-02829
