Genomic Mechanisms Of Resistance To Neoadjuvant Leuprolide Plus Abiraterone In Locally Advanced Prostate Cancer.

98Background: Blocking both gonadal and extragonadal androgens with leuprolide and abiraterone acetate (AA) is approved by the FDA to treat mCRPC. Applying this treatment in the neoadjuvant setting reduced intratumoral testosterone levels in our Phase 2 trial, but pathologic CRu0027s were rare and minimal residual disease was observed in some patients. Methods: We performed laser capture microdissection to isolate pure foci of residual tumor cells from 19 patients who underwent RP following 24 weeks of leuprolide plus AA. We also isolated 19 foci of matched benign glands as germline controls. In 15 of the 19 cases, we dissected 2 spatially-distinct foci of residual tumor. We then performed whole exome sequencing to assess somatic mutations and copy number variations (CNVs). Results: A diversity of genomic resistance mechanisms were observed. Resistance to AA as predicted by mutation of the ligand binding domain of AR was observed in only one case. In contrast, the majority residual tumor foci harbored CNVs co...