Abstract 3074: Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts
Authors: McMullin Ryan , Gupta Himanshu , Rajpurohit Yashoda , Nguyen Holly , Brown Lisha , Sondheim Daniel , Michael Gormley , Ricci Deborah , Thomas Shibu , Eva Corey 
Published: July 2016

Results from clinical and preclinical investigations suggest potential survival benefits from more aggressive early treatment of some patients. Our objective was to evaluate in vivo the efficacy of adding docetaxel (DOC) or ARN509, alone or in combination, to primary androgen ablation and to investigate the associated molecular response and resistance.

We used hormone-sensitive LuCaP patient-derived prostate cancer xenografts (PDXs) models 35, 77, and 147 that all express AR but differ significantly in responses to castration (CX) and exhibit diverse molecular characteristics. Tumors were grown in intact mice and when established, mice were randomized for CX alone or CX with DOC or ARN-509, or their combination. Tumor volume (TV), and serum PSA responses were monitored. Tumors were harvested 5 days post-treatment (d5) and at end of study (EOS) for analyses.

Our results show differential efficacy of the treatments, mimicking the heterogeneity of clinical response. LuCaP 77 progression was inhibited by CX and the additional treatments (TXs) further inhibited TV, with the most decreased TV and PSA detected in the combination group. When compared to CX, CX combined with ARN509 demonstrated the most significantly improved survival benefit (10w vs 16.5w median survival; HR = 0.2, p&lt;0.001), while CX combined with DOC resulted in a smaller survival benefit (10w vs 12.5w, median survival HR = 0.5 p = 0.036). The combination TX did not result in improved survival due to negative health side effects that resulted in early sacrifice. LuCaP 147 exhibited similar responses to CX as LuCaP 77 but only small additional inhibition of TV with the combination TXs and no significant survival improvements over CX alone. LuCaP 35 was the most responsive to CX and the additional treatments did not enhance the TV inhibition, decreases in serum PSA or survival.

Preliminary IHC analyses of the early response (d5 tumors) did not show significant decrease in AR or GR in any of the PDXs but decrease in PSA indicated the efficacy of androgen suppression. Decreased proliferation (Ki67) was detected in LuCaP 77 and LuCaP 147 after CX and more pronounced decreases in the combination vs CX groups in LuCaP 77 and ARN509 and the combination vs CX in LuCaP 147 with no difference detected in LuCaP 35. Analyses of early gene expression responses at d5 by qPCR revealed changes specifically associated with single and combination treatment with ARN509 in LuCaP 77 for both AR-regulated genes (FKBP5, PCNA, and AKR1C3) and proliferation-associated genes (UBE2C3 and NUSAP1). Further analyses of the responses and alteration of genes and proteins associated with AR signaling, proliferation and drug resistance at d5 and EOS are ongoing.

Citation Format: Ryan McMullin, Himanshu Gupta, Yashoda Rajpurohit, Holly Nguyen, Lisha Brown, Daniel Sondheim, Gormley Michael, Deborah Ricci, Shibu Thomas, Corey Eva. Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3074.