New Test Can Determine Whether Expensive Treatments Will Work In Metastatic Cancer
Luo and Antonarakis:
Blood test could save men the trouble and expense of trying a drug that won’t work.
For men with metastatic prostate cancer that is growing despite hormonal therapy, there are two drugs that can help: enzalutamide and abiraterone. However, they are very expensive — costing as much as $100,000 a year — and not every man responds to either drug. Until now, the only way doctors could determine which one of these drugs to use was to prescribe one and see if it worked, and if it didn’t, to try the other. But thanks to groundbreaking research led by Brady scientists Jun Luo, Ph.D., Emmanuel Antonarakis, M.D., and colleagues, there is now a simple blood test that can save these men time and money, and can point the w ay to more effective therapy. This important study was published in September in the New England Journal of Medicine. "Although both of these drugs tr eat metastatic castrate-resistant disease, they each work a little differently," says Luo. "Enzalutamide targets the androgen receptor directly, and abiraterone is something called an androgen synthesis inhibitor; it diminishes the amount of androgen that can bind to the androgen receptor." Resistance to both of these pricy drugs has been observed, "but the reason for this resistance was unclear," until the Hopkins scientists found the common thread on the molecular level. For years, Luo has studied variants of the androgen receptor that bypass the usual mechanisms of activation; they lack the proper binding site for androgen. A particular androgen receptor variant, called AR-V7, is associated with resistance to both drugs, and Luo, Antonarakis, and colleagues have developed an assay to look for AR-V7 in the blood. Antonarakis recently presented their results at the American Society of Clinical Oncology’s annual meeting in Chicago.
In the study, nearly 39 percent of 31 men taking enzalutamide and 19 percent of men taking abiraterone had detectable AR-V7 in the prostate cancer cells circulating in their bloodstream. "Of the men on enzalutamide, those who were AR-V7-positive had poorer PSA response rates compared to the others," says Antonarakis. "They also had shorter progression-free survival compared to men with no detectable AR-V7." Similarly, men with detectable AR-V7 levels who were taking abiraterone did not have as much of a dr op in their PSA as other men, and they, too, had shorter progression-free survival. To make sure that AR-V7 was the key, Luo and Antonarakis adjusted their analysis to account for numerous other factors, and found that the men who w ere AR-V7-positive had "independently inferior responses to the two drugs" than men whose blood showed no AR-V7.
"Because the turn-around time for this assay is only
about three days, we believe that this test could be readily
used in the near future for any patient who is
contemplating therapy with enzalutamide or abiraterone.
If they test positive for AR -V7, these men could potentially
be steered toward alternative treatments, such as
immunotherapy, chemotherapy, or radiotherapy."
Luo and Antonarakis also tested blood from the men during and after their therapy with enzalutamide and abiraterone, and found that some men — six out of 42 — who had been AR-V7-negative before treatment changed during the course of ther apy and became AR-V7-positive. "These men had intermediate clinical outcomes," Luo says, "better than those who started out as AR-V7-positive, but worse than those who remained AR-V7-negative during treatment. The scientists also found that AR-V7 was relatively common among men with metastatic, castrate-resistant prostate cancer. Before this study, "it was thought that the prevalence of AR splice variants was very low," says Antonarakis. "But we showed that the prevalence of AR-V7 actually increases after treatment with abiraterone and enzalutamide." The variant is present in about 12 percent of men who have not received either of these drugs , he adds, "but it appears in about 67 percent of men after exposure to both abiraterone and enzalutamide." AR-V7 was first discovered by Luo in 2008, but at that time , scientists did not recognize the clinical significance of androgen receptor splice variants. "This study is the first to suggest that AR-V7 can be used as a pr edictive marker in men with advanced prostate cancer," Luo says. "If these preliminary findings are replicated by other groups using a larger number of patients, ARV7 could eventually be used as a bio - marker to predict primary or acquired resistance to androgen pathway-targeted therapies." Much additional work needs to be done, he adds. "First, we will need to validate our assay, incorporating the test into larger, prospective therapeutic trials of both abiraterone and enzalutamide."
In other research, the investigators plan to study the role of AR-V7 in predicting resistance to chemotherapy in prostate cancer patients. "Because the turn-around time for this assay is only about three days, we believe that this test could be readily used in the near futur e for any patient who is contemplating therapy with enzalutamide or abiraterone," says Antonarakis. "If they test positive for AR-V7, these men could potentially be steered toward alternative treatments such as immunotherapy, chemotherapy, or radiotherapy." This research was supported by the Prostate Cancer Foundation. Additional authors on the study included Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen, Helen L. Fedor, Tamara L. Lotan, Qizhi Zheng, Angelo M. De Marzo, John T. Isaacs, William B. Isaacs, Rosa Nadal, Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, and Mario A. Eisenberger.