A recent cross-sectional study of men treated for metastatic CRPC (mCRPC) at the Memorial Sloan Kettering Cancer Center in New York, New York, strengthened the case that androgen-receptor splice variant 7 (AR-V7) plays a role in tumors’ ARS inhibitor drug resistance and is a promising biomarker for informing treatment selection decisions. The findings, published in JAMA Oncology, show that CTC expression of AR-V7 protein predicts ARS inhibitor therapy failure. Furthermore, CTC AR-V7 is associated with longer survival times among patients who were treated with taxane-based chemotherapy (overall survival [OS]: 8.9 months versus 4.6 months; P = .035).
The study utilized immunofluorescence protein assay, whereas previous work with CTC AR-V7 has used immunohistochemical (IHC) testing. While the findings are exciting, they must now be validated in prospective trials.
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“There is mounting evidence on the role of AR-Vs as drivers of castration-resistance,” said William Douglas Figg, Sr, PharmD, head of the Molecular Pharmacology Section and deputy branch chief in the Genitourinary Malignancies Branch at the NCI’s Center for Cancer Research in Bethesda, Maryland, in an e-mail to Cancer Therapy Advisor. “Preclinical studies in 22RV1 cells that express both the full-length androgen receptor (AR-FL) and variant (AR-V7) suggest that inhibiting both AR-FLs and variant is necessary to inhibit tumor growth.”
He noted that cell-line studies show that AR-V7 confers resistance to both enzalutamide and abiraterone treatment, and niclosamide—a potent inhibitor of AR-V7—can re-sensitize resistant cells to both drugs.
In a commentary essay about the study, Dr Figg noted that AR-V7 itself is a promising target for drug development, and that this could change the treatment-selection implications of the AR-V7 biomarker.4
“The investigators suggest that AR-V7 status can be used to help guide optimal treatment choices by eliminating abiraterone and enzalutamide as potential therapies in AR-V7 positive status patients,” wrote Dr Figg. “Another viewpoint is that if AR-V7-targeting therapies become available then AR-V7 as a biomarker should not exclude abiraterone and enzalutamide treatment in AR-V7 positive patients; rather it should include these treatments along with an AR-V7-targeting therapy. AR-V7 detection could then help prevent treatment failure seen with abiraterone and enzalutamide.”
A phase 1 clinical trial is underway to demonstrate the efficacy of the combination of niclosamide with enzalutamide, and whether niclosamide reduces the amount of AR-V7, thereby promoting the anti-tumor effects of enzalutamide.
“It remains to be determined the effect of the combination treatment on AR-V7 expression, and monitoring for this potential biomarker is warranted as we move forward to develop novel AR-V7 inhibitors,” Dr Figg said.
Dr Armstrong is leading a multicenter prospective clinical validation study for several AR-V7 biomarker platforms among patients with mCRPC—one of several such validation studies now underway to assess which circulating biomarkers can best help to personalize clinical decision making in prostate cancer management.
“It is not a simple question,” cautioned Dr Armstrong. “Each assay has different sensitivity and clinical data and some men who are AR-V7 positive may still respond to these agents, and many men without AR-V7 detection can still be resistant to these agents.”
