A blood test used to detect AR-V7 in men with advanced prostate cancer may indicate which patients will fail to respond to enzalutamide and abiraterone.
Testing for a protein variant in the blood has the potential to guide treatment for men with metastatic, castration-resistant prostate cancer by predicting which patients are likely to be resistant to the latest standard therapies, a recent study finds.
In the study, two groups of 31 men with previously treated metastatic prostate cancer were given either enzalutamide (Xtandi; Medivation, Astellas) or abiraterone (Zytiga; Janssen). All patients who failed to respond to treatment (12 in the enzalutamide group and 6 in the abiraterone group) had circulating tumor cells that tested positive for androgen-receptor splice variant 7 (AR-V7) mRNA. This splice variant encodes a hormone-independent androgen receptor isoform. The AR-V7–positive patients had significantly shorter progression-free and overall survival than AR-V7–negative patients. The findings were published in The New England Journal of Medicine in September.
“We've known for the last 3 years that about 10% to 20% of advanced prostate cancer patients get no benefit from standard therapy,” says Emmanuel Antonarakis, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, MD, and the study's lead author. “But up until this point we didn't have a biomarker to tell physicians who those patients would be.”
Enzalutamide binds to the androgen receptor, interfering with ligand binding and inhibiting the growth of prostate cancer cells. Abiraterone interferes with local androgen production, depriving androgen receptor of its ligand. However, these drugs appear ineffective in patients with AR-V7 because the variant protein lacks the ligand binding domain and is active in a hormone-independent manner. Even patients who initially respond to therapy eventually acquire resistance, possibly due to the emergence of AR-V7.
If AR-V7 is validated as a biomarker for resistance, physicians could administer a blood test and select alternative treatments, such as chemotherapies, for patients who test positive for it, says Antonarakis. The test could also be used to monitor patients taking enzalutamide or abiraterone to predict when they might stop responding.
Although the findings are “very exciting,” large, prospective studies are needed to validate the results, says Tomasz M. Beer, MD, director of the Prostate Cancer Research Program at Oregon Health & Science University in Portland.
“It's important to recognize that this is an initial discovery paper with a small number of patients that hasn't been confirmed independently,” he says. “It's important that patients know that the test is not at a point where it could be responsibly used in making patient care decisions.”
Antonarakis acknowledges that larger studies are needed to support possible FDA approval, but in the meantime he is working to secure Clinical Laboratory Improvement Amendments (CLIA) certification for the blood test and make it available to other labs over the next year.
“CLIA certification gives us the right to test samples from patients and give out the results,” he says. “We're now looking for a pharmaceutical or biomarker company partner to license and commercialize the test.”