AR-V7 status predicts abiraterone, enzalutamide response in mCRPC
medwireNews: Men positive for androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) derive little benefit from abiraterone or enzalutamide in the treatment of metastatic castration-resistant prostate cancer (mCRPC), US researchers report.
Andrew Armstrong (Duke University, Durham, North Carolina) and colleagues write in the Journal of Clinical Oncology that “such men with mCRPC should be offered alternative treatments.”
The prospective, blinded PROHPECY study included 118 men with progressive, high-risk mCRPC who were starting treatment with abiraterone acetate (n=55), enzalutamide (n=58), or both (n=5) at five academic medical centers in the USA.
Of these, 24% were AR-V7 positive using the Johns Hopkins University (JHU) modified-AdnaTest CTC AR-V7 messenger (m)RNA assay and 9% were AR-V7 positive according to the Epic Sciences CTC nuclear-specific AR-V7 protein assay (Epic, San Diego, California). The percentage agreement between the two assays was 82%, with 17 of the 19 discordant results being JHU AR-V7 positive but Epic AR-V7 negative.
During a median 19.6 months of follow-up, 102 (86%) patients experienced clinical or radiographic disease progression or died.
Median progression-free survival was significantly shorter among AR-V7-positive patients than among AR-V7-negative patients, at 3.1 versus 6.9 months with the JHU assay and 3.1 versus 6.1 months with the Epic sciences assay.
Corresponding overall survival times were 10.8 versus 27.2 months with the JHU assay and 8.4 versus 25.5 months with the Epic Sciences assay.
After adjustment for CELLSEARCH circulating tumor cell enumeration and Halabi risk score, the researchers found that AR-V7 carriers had a 1.9-fold increased risk for disease progression or death relative to noncarriers when their status was determined using the JHU assay and a 2.4-fold increased risk when the Epic Sciences assay was used. The risks for death were 4.2- and 3.5-fold higher, respectively.
Armstrong and team also observed that prostate-specific antigen and soft tissue responses were recorded in 11% and 6% of the men positive for AR-V7 by the JHU assay, respectively, whereas none of the men positive by the Epic Sciences assay experienced either response. By comparison, the response rates were 21–28% among the AR-V7–negative patients by either assay.
Of note, the proportion of men positive for AR-V7 at progression was higher than that at baseline, with the variant detected among 34% of 77 evaluable men using the JHU assay and 20% of 69 evaluable men using the Epic Sciences assay. The investigators say this finding implies “the induction or selection of AR-V7 expression.”
Armstrong et al conclude: “Knowledge of AR-V7 status may optimize treatment selection beyond clinical measures of prognosis and disease burden.”
They add: “The PROPHECY study represents a multicenter effort that provides prospective, blinded clinical validation around such an approach and suggests that both the JHU CTC AR-V7 mRNA assay and the Epic CTC nuclear-specific AR-V7 protein assay provide clinical utility around the anticipated outcomes with therapy.”
By Laura Cowen
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