San Diego, CA—A preliminary study from a highly respected group of researchers suggests that a simple blood test for the androgen receptor splice variant-7 (AR-V7) in the AR gene can identify men with castrate-resistant prostate cancer (CRPC) who will not respond to enzalutamide (Xtandi). If these results are confirmed in a larger population, the test could help to differentiate among patients who could and could not benefit from this drug, avoid unnecessary costs, and allow the patient to move on to an effective drug. The data were presented for the first time at the 2014 American Association for Cancer Research annual meeting.
“AR-V7 is detectable in circulating T-cells in a subset of CRPC patients, and seems to predict resistance to enzalutamide. We believe these data have immediate clinical implications, in that we can steer patients who test positive for this splice variant away from enzalutamide and offer them chemotherapy and radiation,” said Emmanuel S. Antonarakis, MD, Associate Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. “Further, the availability of a blood biomarker for AR-V7 could fuel the development of novel AR therapies,” Dr Antonarakis added.
The use of enzalutamide for CRPC in the predocetaxel space is off-label. However, approval for this indication may be forthcoming. Currently, 3 other therapies are approved for this indication, which include abiraterone (Zytiga) plus prednisone, radium-223 (Alpharadin), and sipuleucel-T (Provenge).
“Even though enzalutamide is considered a very effective drug for some patients, about 20% of patients do not respond,” Dr Antonarakis said.
He noted that many potential reasons for resistance to the drug have been proposed, but he and his team have focused on splice variants of the AR gene. “Our studies suggest that AR-V7 is the most important variant related to resistance to enzalutamide,” Dr Antonarakis said.
A 2-part assay was used to detect AR-V7 in circulating T-cells: the Dana Test Prostate Cancer Select and the AdnaTest ProstateCancer Select kits. The study enrolled 31 men with CRPC who were planning to initiate treatment with enzalutamide. Circulating T-cell samples were provided at baseline, time of response, and time of resistance. The data that Dr Antonarakis presented were derived from baseline circulating T-cell samples.
Of the 31 patients, 12 (39%) had detectable AR-V7 in their circulating T-cells, and 19 (61%) did not. Among patients who were previously treated with abiraterone, the risk of detectable AR-V7 increased to 55%, whereas it was detectable in only 9% of patients who were abiraterone-naïve.
According to the Response Evaluation Criteria in Solid Tumors (RECIST), no tumor shrinkage was seen in any patient with detectable AR-V7. Every patient who had a prostate-specific antigen (PSA) response was wild-type for AR-V7, whereas only 1 of the patients with detectable AR-V7 had a PSA response. The presence of detectable AR-V7 was associated with a 7-fold risk of PSA progression and an 8.5-fold risk of clinical progression.
A multivariate analysis identified 3 factors associated with lack of response, including detectable AR-V7, baseline PSA level, and previous abiraterone treatment. The 2 factors associated with progression-free survival included the presence of AR-V7 and previous treatment with abiraterone.
