Over the last several years’ prostate cancer treatment options for men with advanced prostate cancer has gone from rags to riches. We now have multiple options for treatment and there is every indication that the number of options will continue to grow.
However, we do see that not all men will respond to all treatments. Given that all of these treatments are very costly and all come with the promise of significant side effects it would be beneficial to be able to know in advanced without having to administer a treatment if a particular treatment will actual benefit a man.
“Enzalutamide (Xtandi) has been hailed as a miracle drug for many patients with advanced prostate cancer, but a significant proportion of men do not receive any clinical benefit from this agent,” said Emmanuel Antonarakis, M.D., an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. “Our data show that AR-V7 seems to predict resistance to enzalutamide in virtually all cases. These findings are clinically relevant and could save patients time and money because oncologists could identify those men that are unlikely to respond to enzalutamide before they receive it and direct them to alternative therapies.”
According to research conducted by Dr. Antonarakis, men with metastatic, castration-resistant prostate cancer who started treatment with enzalutamide and had a molecule called AR-V7 present in their circulating tumor cells (CTCs) prior to starting treatment had a worse response to The enzalutamide compared with those who had no detectable AR-V7. These results were presented at the AACR Annual Meeting 2014 where I was in attendance, thus I have not had the opportunity to post over the last week.
According to Antonarakis and many others our hormones (androgens), such as testosterone, are the main drivers of prostate cancer. These androgens work by binding to a protein called the androgen receptor (AR), which then attaches to certain regions of the DNA of the prostate cancer cell, fueling its growth and division. This AR-V7 protein in question is a shortened form of the AR protein. It is missing the part of AR that testosterone binds, which is the same part that enzalutamide binds, but it can still attach to DNA and fuel cell growth and division, even when testosterone is not bound to it.
This was a small study enrolling only 31 men with metastatic, castration-resistant prostate cancer who were about to begin enzalutamide treatment. Blood samples were obtained from each man prior to starting treatment with enzalutamide, at the time of the man’s maximum response to treatment, and at the time of disease progression. CTCs were isolated from blood samples and analyzed for the presence of AR-V7 mRNA, an intermediate between the AR gene and the AR-V7 protein.
The researchers found that 12 of the 31 men had AR-V7 mRNA detectable in CTCs obtained prior to the start of enzalutamide treatment. These AR-V7-positive men had worse responses to enzalutamide compared with men who had no AR-V7 mRNA detected in CTCs.
Levels of prostate-specific antigen (PSA), a measure of prostate cancer disease activity, failed to drop in the blood of all 12 AR-V7-positive men, whereas PSA levels dropped by 50 percent or more in 10 of the 19 AR-V7-negative men.
They also found that AR-V7 positive men also had their disease progress sooner (as assessed by bone scan or computed tomography) compared with those who were AR-V7-negative: Time to radiographic progression was 2.1 months compared with 6.1 months.
Antonarakis also said “Before we can conduct the large-scale prospective trials needed to verify our results, we need to have the test that we used to detect AR-V7 mRNA in CTCs certified in a Clinical Laboratory Improvement Amendments (CLIA) setting to ensure the necessary quality control. We are currently in the process of doing this and we hope that things will run smoothly so we can continue to move forward.”
He also added that, “We are also conducting a small study to see whether AR-V7 might predict resistance to another AR-targeted therapy, abiraterone