Expression of the nuclear androgen-receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) found in the blood of patients with advanced prostate cancer predicts the patients will fail to respond to the commonly prescribed androgen receptor signaling (ARS) inhibitors, but will have superior survival if treated with a taxane therapy.
These findings were recently published in JAMA Oncology in the study “Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer.”
Almost all patients with metastatic prostate cancer progress to metastatic castration-resistant prostate cancer (mCRPC), where the standard of care includes the ARS inhibitors abiraterone and enzalutamide, and taxanes. These therapies are known to be effective in extending patients’ lifes, but 20 to 25 percent of patients fail to respond in first-line approaches. This number increases to 60 to 70 percent in those receiving second-line therapy. When the determination of nonresponse is delayed in these patients, the chance to benefit from alternative treatments may be compromised.
Prostate cancer is an androgen-dependent disease. However, there are splice variants of the androgen receptor that can be activated independent of ligand binding, making cells resistant to androgen deprivation therapies. In fact, AR-V7 has been recently linked to resistance to the ARS inhibitors abiraterone and enzalutamide when expressed in the CTCs of men with mCRPC.
The research team at the Memorial Sloan Kettering Cancer Center in New York analyzed samples from 161 patients with mCRPC about to start ARS inhibitor or taxane therapy as a first, second, or third-line treatment. In total, 193 blood samples were collected from the patients and were analyzed for CTCs with the AR-V7 biomarkers using Epic Sciences’ liquid biopsy platform. This technique allowed researchers to analyze every nucleated cell found in patients’ blood samples, including rare forms of CTCs that were clustered or lacked common protein markers.
“We wanted to determine AR-V7’s potential for guiding treatment decisions by assessing a real-world sample from any mCRPC patient coming to Memorial Sloan Kettering Cancer Center,” Ryan Dittamore, vice president of translational research and clinical affairs at Epic Sciences and the study’s lead author, said in a press release.
The researchers observed AR-V7 positive CTCs in 18 percent of all examined patients, who all failed to respond to abiraterone and enzalutamide, presenting shorter overall survival than AR-V7 negative patients. Furthermore, AR-V7-positive patients were found to survive for longer periods when treated with taxane-based chemotherapy instead of ARS inhibitors.
“This study indicates the potential for an AR-V7 predictive test to enable advanced prostate cancer patients to avoid ineffective therapies and to receive chemotherapy at an earlier stage when it may be more beneficial. Today, no predictive diagnostic tests are available to improve treatment selection in prostate cancer — and they are urgently needed,” said Epic Sciences CEO Murali Prahalad, Ph.D.