Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).

Abstract

200 Background: BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes. Methods: Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed. Results: Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy. Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%). HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table). In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS). Conclusions: These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation. These results require prospective confirmation. [Table: see text]