Molecular and clinical characterization of metastatic castration-resistant prostate cancer (mCRPC) patients achieving deep PSA responses to bipolar androgen therapy (BAT).

Abstract

127 Background: BAT is an emerging treatment strategy for men with mCRPC, whereby testosterone concentrations are cycled from supraphysiologic to castrate levels each month. BAT has been shown to be safe, and induces clinical responses in a proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of mCRPC pts that achieved deep PSA responses on BAT. Methods: We identified N= 22/114 (19%) mCRPC pts who achieved >70% PSA reductions on treatment with BAT. All pts were treated on-protocol at Johns Hopkins using 400mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Pts remained on study until clinical or radiographic progression, as per protocol. Clinical-grade molecular sequencing was obtained using commercially available assays. Results: Next-generation somatic DNA sequencing was obtained on 15/22 (68%) pts. Of these 15 pts with sequencing data who achieved a >70% PSA response on BAT, 14/15 (93%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among patients with measureable disease (N=15), 10 pts (67%) achieved an objective response including one pt with a complete response. The median radiographic progression-free survival (rPFS) of these deep PSA responders on BAT was 11.3 (95% CI, 7.9-25) months. Conclusions: We observed an enrichment of TP53 and/or HRD mutations in mCRPC pts with extreme PSA responses to BAT, with durability lasting about a year These data support the hypothesis that BAT may work best in DNA repair-deficient mCRPC pts. Further study of BAT in biomarker selected mCRPC populations (i.e. TP53/HRD mutated) is warranted. [Table: see text]