AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer

March 2015, Vol 6, No 2

Orlando, FL—Experts are hopeful that the field of prostate cancer will soon be catching up to breast cancer and some other tumor types with regard to genomic markers.

A study featured at the 2015 Genitourinary Cancers Symposium suggests that the an­drogen receptor (AR) abnormality known as “AR-V7” will turn out to be a predictive marker to help in treatment selection for patients with metastatic castration-resistant prostate cancer (CRPC).

The study showed that the presence of AR-V7 in circulating tumor cells was predictive of sensitivity to chemotherapy with the taxanes docetaxel (Taxotere) and cabazitaxel (Jevtana) in men with metastatic CRPC.

A previous study by the same team of researchers showed that patients whose circulating tumor cells harbored AR-V7 had primary resistance to AR-directed therapy with enzalutamide (Xtandi) and abiraterone (Zytiga); the study was published late last year (Antonarakis ES, et al. N Engl J Med. 2014;371:1028-1038).

In Search of Biomarkers

Taken together, the studies suggest that patients who are AR-V7–positive should be offered chemotherapy with one of the taxanes instead of enzalutamide or abiraterone, whereas patients who are AR-V7–negative can be offered either type of therapy safely.

Lead investigator Emmanuel S. Antonarakis, MBBCh, Assistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said, “We urgently need markers that predict which therapies are going to be effective, and which will not, in individual patients with prostate cancer. AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future.”

Dr Antonarakis noted that the findings related to AR-V7 need to be validated in a prospective multicenter trial.

No commercial test for AR-V7 is currently available. These researchers and other investigators are working on developing a CLIA (Clinical Laboratory Improvement Amendments)-approved test for AR-V7, Dr Antonarakis said.

“Taxanes may be more efficacious than AR-directed therapy in AR-V7–positive men,” Dr Antonarakis stated. “We need to prospectively validate this marker for therapy selection. The utility of the test will be greater in positive patients, if confirmed, whereas the utility in AR-V7–negative patients is not so great.”

Study Details

The present study included 37 men with metastatic CRPC who were initiating chemotherapy with docetaxel or enzalutamide; 17 of 37 (46%) patients were found to be AR-V7–positive. In general, at least 33% of patients with CRPC are AR-V7–positive.

The primary end point of the study was the associations between AR-V7 status and prostate-specific antigen (PSA) response rates; a ?50% reduction in PSA from baseline was considered to be a positive PSA response to therapy. Other end points were progression-free survival (PFS) as measured by PSA levels and by clinical or radiographic progression.

PSA responses were achieved in 41% of AR-V7–positive and 65% of AR-V7–negative patients. The median PSA-based PFS rates were comparable between these 2 groups—4.5 months versus 6.2 months, respectively; the median PFS was also comparable: 5.1 months versus 6.9 months, respectively.

When the investigators incorporated data from their previous study of 62 men who received abiraterone or enzalutamide, clinical outcomes were superior in AR-V7–positive men who received taxanes versus abiraterone or enzalutamide, whereas outcomes were not significantly different for AR-V7–negative men who received either type of therapy.

A striking difference in PSA response was observed between the 2 types of therapy in AR-V7–positive men; 41% of patients showed positive response with the taxanes versus 0% (P <.001) with enzalutamide or abiraterone.

The median PSA-based PFS and the median PFS were significantly ­longer in AR-V7–positive men who received taxanes (P = .001 and P = .003, respectively).

“The AR-V7 biomarker is better at separating patients requiring AR-directed therapy versus chemotherapy. If a patient is AR-V7–positive, he has a greater chance of progression on enzalutamide or abiraterone compared with taxanes. In fact, he has a 79% lower chance of progression on a taxane and a 4.8-fold greater increase in risk of progression on enzalutamide or abiraterone,” Dr Antonarakis commented. “In AR-V7–negative patients, there is no difference in PFS between taxanes or AR-directed therapy.”

According to these results, the presence of AR-V7 in circulating tumor cells is not associated with primary re­sistance to the taxanes; it is, however, ­associated with primary resistance to AR-directed therapy.

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