Background Androgen signaling is a central driver in CRPC. We performed a study to determine the effect of the antiandrogen MDV 3100 on bone marrow infiltrating CRPC. Methods From February 2010 to June 2011, we performed an open-label, observational study of 60 bmCRPC patients (pts), who underwent transilial bone marrow biopsy (BMB) at baseline and 8 weeks of treatment. Pts received MDV3100 160mg orally once daily. The primary objective was to evaluate androgen signaling in bone marrow infiltrating cancer and testosterone in blood (BT) and bone marrow (BMT) and correlate findings with clinical observations. Androgen receptor (AR), CYP17 and phospho Src (pSrc) expression were assessed by immunohistochemistry, and BT and BMT by liquid chromatography mass spectrometry. Findings Maximal PSA decline of Δ50% occurred in 29 (48%) of 60 pts, and α90% in 13 (22%). Tumor involvement in BMB was detected in 28 (47%) pretreatment BMBs. Paired tumor infiltrated BMBs were found in 23 (38%) pts. Pretreatment androgen signaling and pSrc tumor expression is shown in Table 1. Pretreatment intense nuclear AR expression combined with α10% CYP17 tumor expression or increased BMT correlate with Δ50% PSA decline (p value 0.02). AR subcellular localization shift from dominant nuclear to cytoplasmic correlate with Δ50% PSA decline (p value 0.05). Increased pretreatment p-Src expression is associated with lack of PSA decline (p value 0.002). Increase in BMT and BT is observed after 8 weeks of MDV3100. (Mean Pretreatment BMT 0.03 ng/ml, Wk8 BMT 0.04 in 33pts, p value 0.0009) (Pretreatment BT 0.05, wk8 BT 0.066 in 37 pts, p value 0.0001) Interpretation Pretreatment expression profile is consistent with persistent androgen signaling in bmCRPC. MDV3100 induces ‘pharmacodynamic’ changes in Androgen Signaling. AR changes likely account for the reported therapeutic effect of MDV3100. These data prompt exploratory combinations of MDV3100 with Androgen Biosynthesis Inhibitors and src inhibitors.

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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2696. doi:1538-7445.AM2012-2696

©2012 American Association for Cancer Research
2012