Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC)

• Published in: Molecular cancer therapeutics 2019-03, Vol.18 (3), p.726-729
• Main Authors: Hahn, Andrew W, Gill, David M, Poole, Austin, Nussenzveig, Roberto H, Wilson, Sara, Farnham, James M, Stephenson, Robert A, Cannon-Albright, Lisa A, Maughan, Benjamin L, Agarwal, Neeraj
• Format: Article
• Language: English
• Subjects: Abiraterone Acetate - pharmacology; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Cell Line, Tumor; Disease-Free Survival; Genotype; Germ-Line Mutation - genetics; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Organic Anion Transporters - genetics; Polymorphism, Single Nucleotide - genetics; Prednisone - pharmacology; Prostate - metabolism; Prostate - pathology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-18-0739

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of are common and predict improved response to first-line abiraterone acetate in men with mCRPC.