Patients with advanced prostate cancer may need periodic imaging scans to catch tumor growth even with stable levels of prostate-specific antigen (PSA), a protein in the blood that doctors routinely monitor for cancer progression, according to an analysis led by researchers at Weill Cornell Medicine and Duke University. In some cases, cancer progression was detected on scans even when PSA levels were undetectable.
The recent study, published in the Journal of Clinical Oncology, analyzed data from more than 2,500 men enrolled 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 (ARCHES and PROSPER) assessed cancer spread or growth on imaging scans, alongside changes in PSA levels during treatment. The researchers examined cases of radiographic progression – when cancer growth or spread is detected by imaging such as X-rays, CT scans or bone scans.
“We found that up to roughly 25% of patients had radiographic prostate cancer progression without any rise in PSA levels, and they had worse outcomes,” said senior author Dr. Cora N. Sternberg, professor of medicine in hematology and medical oncology at Weill Cornell, and a medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “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.
Dr. Andrew Armstrong, professor of medicine at Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, is the paper’s first author.
Clinical trial data suggests silent growth
The ARCHES trial included patients whose prostate cancer had metastasized but still responded to hormone therapy, which lowers testosterone levels or blocks the cancer’s ability to use testosterone signals to grow. Of these patients receiving enzalutamide, a subset experienced cancer progression on imaging despite stable, low or minimally changing PSA levels.
The researchers found similar results in the PROSPER trial, which enrolled patients with non-metastatic castration-resistant prostate cancer, meaning their prostate cancer no longer responded to hormone therapy, but their cancer had not spread to other organs based on conventional imaging.
Patients taking enzalutamide whose cancer progressed on imaging had worse overall survival than those whose cancer had not, regardless of PSA changes. The study also found that patients often felt well without new symptoms, despite the cancer advancing. Since the findings in both groups were similar, this may be a broad issue across advanced prostate cancer.
To understand this phenomenon, the researchers looked for clues about why PSA and cancer progression may become disconnected. They suspect some tumors evolve resistance mechanisms that allow them to grow independently of androgen receptor signaling. These cancer cells may produce little or no PSA while continuing to spread. This process, sometimes called lineage plasticity or neuroendocrine transformation, requires continued investigation.
More accurate patient monitoring
Based on the results, the investigators suggest that patients receiving potent androgen receptor inhibitors such as enzalutamide may benefit from periodic imaging in addition to routine PSA monitoring, particularly during the first two years of treatment. They propose that future clinical guidelines should reconsider how PSA increase defines cancer advancement and provide clearer recommendations for imaging frequency.
“We did not expect to see these rates of radiographic progression with low PSA and sometimes even zero PSA,” said Dr. Sternberg, who is also a member of the Sandra and Edward Meyer Cancer Center. “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.”
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Cora N. Sternberg.
Heather Lindsey is a freelance writer for Weill Cornell Medicine.
