A blood test that measures the spliced variant of an androgen receptor called AR-V7 in circulating tumor cells successfully predicted resistance to commonly used hormonal therapy agents in advanced prostate cancer, a validation study confirmed.
In the multicenter PROPHECY trial, researchers found that the use of two blood-based assays for measuring AR-V7 — the Johns Hopkins modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear AR-V7 protein assay — demonstrated that AR-V7 positivity is associated with resistance to the androgen receptor (AR) pathway inhibitors abiraterone and enzalutamide.
“We confirmed that AR-V7, if positive, was associated with a lack of benefit with these therapies – a very low probability of a response to these hormone drugs, a short time to progression, and very low survival for men who test positive,” Andrew Armstrong, MD, Duke Cancer Institute, told MedPage Today.
Armstrong, who led the study, said the AR-V7 test allows physicians to make more informed recommendations about alternative therapies to patients who test positive. “And those alternatives might include therapies already available, including docetaxel chemotherapy,” said Armstrong. “Or physicians may want to enroll patients in clinical trials of some new agents that might have more promise than using a drug that’s not likely to work.”
Results of the study were published in the Journal of Clinical Oncology.
Androgen receptor (AR) pathway inhibitors abiraterone and enzalutamide have become the standard of care for men with high-risk metastatic castration-resistant prostate cancer. However, as Armstrong and colleagues pointed out, resistance to these therapies develops in men who have been previously treated with these agents, leading to lower response rates and shorter progression-free and overall survival times.
“And there is a lot of cross-resistance between these therapies, meaning that when one of the drugs stops working, the other drug often won’t work very well,” Armstrong said, adding that it is very difficult to predict when cross resistance will occur.
Earlier studies, including from Johns Hopkins University and Memorial Sloan Kettering Cancer Center, suggested that AR-V7 can be detected in circulating tumor cells and predict resistance. PROPHECY was designed to validate those findings.
Armstrong and colleagues enrolled 118 patients with high-risk metastatic castration-resistant prostate cancer. Of these patients, 58 were starting treatment with enzalutamide, 55 with abiraterone, and five were receiving both concurrently.
Median progression-free survival (PFS) was 5.8 months (95% CI 4.1-7.6 months), and median overall survival was 20.3 months (95% CI 17.0-27.2 months) for the overall cohort, which, Armstrong and his colleagues noted, reflected “the high risk features of this population.”
In the overall study cohort, approximately 10%-24% of men were AR-V7 positive, depending on which of the assays were used. For both PFS and OS, there were significant differences between AR-V7 positive and AR-V7 negative men for both assays.
For the Johns Hopkins AR-V7 assay, the median PFS for AR-V7–positive versus AR-V7– negative patients was 3.1 vs 6.9 months, respectively (HR, 2.4; 95% CI 1.5-3.7). For the Epic AR-V7 protein assay, the median PFS for AR-V7–positive versus AR-V7–negative patients was 3.1 vs 6.1 months, respectively (HR, 2.5; 95% CI 1.3-4.7).
Median overall survival for AR-V7– positive versus AR-V7–negative patients was 10.8 vs 27.2 months, respectively (HR, 3.9; 95% CI 2.2-6.9), for the Johns Hopkins assay, while the median overall survival for AR-V7– positive versus AR-V7–negative patients was 8.4 vs 25.5 months, respectively (HR, 3.4; 95% CI 1.6-7.0), for the Epic assay.
AR-V7 detection by both the Johns Hopkins and Epic assays was independently associated with shorter PFS (HR 1.9, 95% CI 1.1-3.3; and HR 2.4, 95% CI 1.1-5.1), respectively. The same was true for overall survival (HR 4.2, 95% CI 2.1-8.5; and HR 3.5, 95% CI 1.6-8.1), for the Hopkins and Epic assays, respectively.
Armstrong noted that the Epic AR-V7 test is now covered by Medicare. “Because of this, and other studies, it has become a clinically useful test for some men,” Armstrong said. “It can be ordered by physicians nationwide, and the results come back reasonably quickly — within a week.”
However, “there are some caveats,” Armstrong told MedPage Today. “It’s not a perfect test for resistance. There are other mechanisms of resistance to these drugs and this only measures one aspect of this resistance. What I really like about the PROPHECY study, which is part of ongoing work, is that we are trying to discover those other mechanisms of resistance beyond AR-V7.”
See article for authors’ disclosures of potential conflicts of interest