In a small clinical trial, scientists found that men with advanced prostate cancer and detection of androgen receptor splice variant-7 (AR-V7) respond to chemotherapy just as well as men who lack the variant.
The findings, the researchers say, may be significant for patients who carry the AR-V7 variant, because they are more likely to develop resistance to one of two hormone drugs routinely used to treat their disease. Results of the trial were published in JAMA Oncology (2015; doi:10.1001/jamaoncol.2015.1341).
“Our study shows that men who have the AR-V7 gene variant and usually don’t respond to either abiraterone or enzalutamide, are not at a disadvantage when given chemotherapy drugs,” said Emmanuel Antonarakis, MD, an oncologist at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.
Seven of the 17 men in the trial who carried the AR-V7 variant and received chemotherapy experienced a 50% reduction in their prostate-specific antigen (PSA) level.
The National Cancer Institute estimates that prostate cancer will be diagnosed in more than 220,000 men in 2015 and more than 27,000 will die from it. Approximately 5% of patients (11,000) with prostate cancer have advanced disease.
The AR-V7 gene variant was discovered in 2008 by researcher Jun Luo, PhD, of the James Buchanan Brady Urological Institute at Johns Hopkins. In a previous study, Luo and Antonarakis found that men with the AR-V7 variant were resistant to hormonal drugs, such as enzalutamide or abiraterone, which are androgen receptor-directed therapies used for treating castration-resistant prostate cancer.
Abiraterone and enzalutamide, said Antonarakis, aim to block the production and function of male hormones. When the AR-V7 variant is present, it codes for shortened proteins that, unlike full-length AR proteins, regulate prostate cancer growth, which is not dependent on male hormones. Therefore, men who have the AR-V7 variant are more likely to be resistant to hormone drugs, rendering them ineffective.
In the new trial, which included 37 men being treated with either docetaxel or cabazitaxel, at the Johns Hopkins Hospital, 17 had detectable levels of the AR-V7 variant in their blood. In comparing men with and without the gene variant, there was no statistical difference in how much patients’ PSA levels declined, how long it took for their cancers to progress, or their overall survival.
In a previous clinical trial of 62 patients with castration-resistant prostate cancer, the same researchers found that 18 AR-V7-positive patients who took either enzalutamide or abiraterone showed no reduction in their PSA levels, indicating that the drugs were not effective in these patients. However, the current study showed that seven of 17 (41%) AR-V7-positive patients receiving chemotherapy achieved a 50% reduction in PSA levels.
Taken together, Antonarakis said, the findings, if confirmed in larger trials, suggest that the presence of the AR-V7 variant could be used someday as a biomarker to improve treatment decision-making for patients with prostate cancer.
The researchers also noted that the two hormone therapies, abiraterone and enzalutamide, are considerably more expensive than chemotherapy. At more than $30,000 for a 6-month treatment, the hormone-based therapies are more than double the chemotherapy costs.