Germline variant alleles may predict response to first-line abiraterone for metastatic prostate cancer

CHICAGO — Germline variant alleles in rs12422149 of SLCO2B1 appeared associated with improved response to abiraterone acetate among men with metastatic castration-resistant prostate cancer, according to study results presented at ASCO Annual Meeting.

Abiraterone acetate (Zytiga, Janssen) is approved for use in combination with prednisone for patients with metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer. However, biomarkers that can better predict treatment response for patients with advanced disease are necessary, according to study background.

A previously published preclinical study by Mostaghel and colleagues showed variant alleles in select single nucleotide polymorphisms for SLCO2B1 — which encodes a protein that mediates transport of endogenous sex hormones and drugs, including abiraterone acetate, into tissue — resulted in higher abiraterone acetate levels in tumor tissue.

A prior exploratory analysis assessed the association between PFS and these variant alleles — rs12422149 and rs1789693 — among abiraterone-treated men with newly diagnosed metastatic castration resistant prostate cancer. Results showed a trend toward prolonged PFS with variant alleles for rs12422149 but not for rs1789693.

In the current analysis, Andrew W. Hahn, MD, an internal medicine resident at University of Utah, and colleagues assessed the correlation of variant alleles in rs12422149 with PFS among a larger, more cohort of men who received first-line abiraterone acetate.

The researchers used a prospective prostate cancer registry at University of Utah to analyze clinical data and samples. They used the Illumina OmniExpress platform to perform genotyping.

Researchers genotyped 401 men with advanced prostate cancer; of these men, 323 (80.5%) were homozygous wild type for rs12422149, 74 (18.5%) were heterozygous, and four (1%) were homozygous variant.

Hahn and colleagues conducted a prespecified multivariate Cox regression analysis of 79 men treated with first-line abiraterone acetate for metastatic castration-resistant prostate cancer.

Sixty-three had rs12422149 GG genotype. In this group, log PSA at abiraterone initiation was 3.22, and 57 (91%) had Gleason scores of 7 to 10.

The other 16 patients had rs12422149 AG genotype. In this group, log PSA at abiraterone initiation was 3.6, and 13 (81%) had Gleason scores of 7 to 10.

Results of this multivariate analysis showed men heterozygous for rs12422149 achieved significantly improved median PFS compared with the homozygous group (8.9 months vs. 6.3 months; HR = 0.46; 95% CI, 0.23-0.94).

“In this first clinical validation of preclinical data reported by Mostaghel [and colleagues], variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate [among] men with metastatic castration-resistant prostate cancer,” Hahn and colleagues wrote. “These hypothesis-generating data require further validation in a larger cohort.” – by Mark Leiser

For more information:

Hahn AW, et al. Abstract 5076. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Mostaghel EA, et al. Clin Cancer Res. 2017;doi:10.1158/1078-0432.CCR-16-2245.

Disclosures: Hahn reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.