457 Preclinical pharmacology of AZD5312, a generation 2.5 antisense oligonucletotide targeting the androgen receptor with differentiated activity from enzalutamide

The androgen receptor is a clinically validated target in prostate cancer; signalling through the androgen receptor remains an important driver of disease progression even in castration resistant disease, as shown by the recent successful phase 3 trials of second generation androgen receptor antagonist enzalutamide and CYP17 inhibitor abiraterone. However, resistance to these agents inevitably emerges, due to a variety of mechanisms including mutations in the receptor and expression of spliced variants that lack the ligand binding domain but still drive AR signalling. Down-regulation of AR using an antisense oligonucleotide has the potential to overcome these resistance mechanisms. AZD5312 causes dosedependent down-regulation of full length AR mRNA and protein, inhibits AR-dependent gene expression, and induces apoptosis in prostate cancer cell lines including LNCaP and VCaP. In 22Rv1 cells, AZD5312 also downregulates the spliced variant AR-v7, and shows a differential effect on a 48gene AR transcriptome signature to enzalutamide, whereas this response is similar in LNCaP cells that only express full length AR. Moreover, AZD5312 inhibits proliferation of 22Rv1 cells, whereas enzalutamide does not. In vivo, AZD5312 down-regulates full length and spliced variant forms of AR, and inhibits PSA protein expression, in the LuCAP86.2 transplantable prostate cancer xenograft model. AZD5312 also reduces AR expression and inhibits the growth of AR-expressing MDA-MB-453 breast cancer xenografts in nude mice supplemented with dihydrotestosterone. In conclusion, AZD5312 is a potent antisense oligonuleotide targeting AR that is therapeutically active preclinically, with differentiated activity from enzalutamide.