AR-V7 Linked to Enzalutamide, Abiraterone Resistance in Prostate Cancer

Emmanuel S. Antonarakis, MD; photo by © ASCO/Silas Crews 2014

Enzalutamide and abiraterone acetate are both approved oral therapies for the treatment of metastatic castration-resistant prostate cancer (CRPC) that target the androgen pathway. Enzalutamide targets the androgen receptor and abiraterone is an androgen biosynthesis inhibitor that targets the C17,20 enzyme.

Resistance to both of these therapies may be associated with the androgen receptor splice variant-7 (AR-V7), a truncated form of the androgen receptor that lacks the ligand-binding domain. Emmanuel S. Antonarakis, MD, assistant professor of oncology at Johns Hopkins University, and colleagues have demonstrated the ability to detect AR-V7 in circulating tumor cells (CTCs) of prostate cancer patients with primary resistance to enzalutamide and abiraterone. Antonarakis presented the data (abstract #5001) at the American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30–June 3 in Chicago.

The study authors also show that AR-V7 is relatively common among men with metastatic CRPC. “This is the first study to document the prevalence of AR-V7 in relation to abiraterone and enzalutamide treatment, and the first study to do so using CTCs” said Antonarakis. “It was previously thought that the prevalence of AR splice variants was very low. Here, we show that the prevalence of AR-V7 increases after treatment with abiraterone and enzalutamide.” According to Antonarakis, AR-V7 is present in about 12% of men who have not received either agent, but increases to about 67% after exposure to both abiraterone and enzalutamide.

In the study, 38.7% of the 31 enzalutamide-treated patients and 19.4% of the 31 abiraterone-treated patients analyzed had detectable AR-V7 in their CTCs. AR-V7–positive patients treated with enzalutamide had poor PSA response rates compared with those that did not have detectable AR-V7 levels (0% vs 52.6%, P = .004). These patients also had shorter progression-free survival compared with those with no detectable AR-V7 levels (median 2.1 months vs 6.1 months, P < .001).

Likewise, those men with metastatic CRPC and detectable AR-V7 levels who were treated with abiraterone also had poor PSA response rates compared with patients with no detectable AR- V7 levels (0% vs 68%, respectively, P = .004), and shorter progression-free survival (median 2.3 months vs not reached, P < .001).

Forty-two men in the study were AR-V7 negative and six of these (14%) switched to AR-V7–positive status during treatment. These patients had an intermediate response, better than those patients who started out as AR- V7 positive, but worse than patients who remained AR-V7 negative during treatment.

The ability of the presence of AR-V7 to serve as a negative prognostic marker remained after adjustment for expression levels of the wild-type full-length androgen receptor.

The enzalutamide and abiraterone cohorts from this study cannot be directly compared, according Antonarakis. “This is because, at our institution, we generally used abiraterone first and enzalutamide later.” As a result, the enzalutamide-treated patients generally had more advanced disease than the abiraterone-treated patients. However, one of the main messages of this abstract is that the detection of AR-V7 is not a rare event. In fact, it is quite common (29% of all CRPC patients tested in the study).

AR-V7 could be used as a biomarker to predict de novo or developed resistance to androgen pathway targeted therapies. First, the authors are validating the AR-V7 CTC assay, incorporating the test into larger cohort prospective therapeutic trials of both abiraterone and enzalutamide. The researchers are also studying the role of AR-V7 in predicting the resistance to chemotherapy in prostate cancer patients.

“Because the turn-around time for our assay is only about 3 days, we believe that this non-invasive test could be readily used in the future for any patient with CRPC who is contemplating therapy with enzalutamide or abiraterone,” said Antonarakis.