Abstract LB-421: Characterization of castrate resistant prostate cancer treated with abiraterone acetate and prednisone
Authors: Efstathiou Eleni , Titus Mark , Tsavachidou Dimitra , Tzelepi Vassiliki , Wen Sijin , Hoang Anh , Molina Arturo , Chieffo Nicole , Smith Lisa A. , Smith BS RN , Karlou Maria Karlou , Troncoso Patricia , Logothetis Christopher J. 
Published: July 2012

Background: Recent observations implicate persistent androgen signaling in metastatic castrate-resistant prostate cancer (mCRPC) progression. Inhibition of CYP 17 lyase with abiraterone acetate (AA) prolongs survival of patients (pts.) with mCRPC progressing after docetaxel (de Bono et al ESMO 2010). Despite initial benefit to AA, most pts. develop disease progression. The purpose of this study is to better understand resistance by characterizing mCRPC in bone marrow of pts. on AA.

Methods: From October 2007 to March 2010, we performed an open-label, study of 57 pts. with metastatic CRPC, who underwent transilial bone marrow biopsy at baseline, 8 weeks and progression. Pts. received AA, 1 g once daily, and prednisone, 5 mg twice daily. The objective was to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate findings with clinical observations. Androgen receptor (AR) and CYP17 expression was assessed by immunohistochemistry, and testosterone concentration by electrospray tandem mass spectrometry. AR copy numbers ( Real-Time PCR) and TMPRSS2-ERG ( FISH) were assessed in available tissues.

Findings: Median overall survival was 555 days (95% CI: 440-965+). Maximal PSA decline of ≥50% occurred in 28 (50%) of 56 pts., and ≥90% in 9 (16%). Homogeneous, intense nuclear AR expression in combination with ≥10% CYP17 tumor expression correlated with longer time to treatment discontinuation (&gt;4 months) in 25 pts. with tumor-infiltrated bone marrow. Pretreatment CYP17 expression of ≥10% in the tumor correlated with increased bone marrow testosterone. Blood and bone marrow testosterone concentration declined to below picogram levels and remained suppressed at progression. AR copy number increased over time in pts. with benefit from treatment as opposed to early progressors (≤ 4 months) where no difference was observed. Over expression of nuclear AR by immunohistochemistry was observed in (9/11) cancers from pts. benefiting, whereas 4/6 cancers from pts. with early progression a significant reduction in nuclear AR was seen. CYP 17 expression was lost in repeat biopsy performed at progression in 6/11 cancers available for analysis from pts. with prolonged response.

Interpretation: The pretreatment expression profile observed is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that AA achieves sustained suppression of testosterone in blood and bone marrow to below picogram levels suggesting that progression is testosterone independent. Increased expression of AR in the context of sustained depletion of bone marrow testosterone by AA favors the hypothesis that "native ligand independent AR signaling" is implicated in abiraterone resistance. Our observations provide rationale for a combinatorial androgen signaling inhibition strategy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-421. doi:10.1158/1538-7445.AM2011-LB-421