Molecular and histopathologic correlates of imaging and biological responses to neoadjuvant GnRH agonist plus enzalutamide for high risk prostate cancer.

Abstract

34 Background: AR directed therapies are standard of care for metastatic prostate cancer, and their use for high-risk localized disease may improve survival. Previous trials showed low rates of complete pathologic responses to neoadjuvant ADT. The underlying biology and molecular features of tumors that fail to respond remain unknown. Methods: Men with localized prostate cancer with high risk features received 6 months of GnRH agonist plus enzalutamide. mpMRI was performed at baseline and prior to RP. MRI-US fusion guided biopsies were performed at study enrollment. RP specimens were sectioned in the same plane as mpMRI. Imaging and anatomical landmarks on pre- and post-treatment mpMRI were used to match targeted biopsies to RPs. IHC stains including AR, GR, and SYP were performed to guide laser capture microdissection (LCM) and characterization of residual disease. DNA was extracted from LCM biopsy and RP tissues. Whole exome sequencing with somatic mutation calling and copy number analysis was performed. Results: Most patients showed incomplete pathologic responses despite reductions in tumor volume. Several patients harbored multiple tumor clones prior to treatment, distinguished by distinct copy number alterations and mutations in biopsies. Alignment of biopsies to pre- and post-treatment mpMRI correlated with imaging response and histopathology of matched RP sections. Minimal genomic divergence from untreated clones on biopsy suggested intrinsic resistance, while extensive divergence indicated selection for pre-existing subclones. Most residual tumor was AR- and GR-positive adenocarcinoma, with some regions of AR-negative Panneth cell-like differentiation positive for synaptophysin. AR-V7 was rare in residual tumor and < 1% cells were positive for KI-67. The most common alteration in all samples was single-copy loss of chromosome 16q overlapping with ZFHX3. Conclusions: Our approach of repeated sampling by matching targeted biopsies to mpMRI demonstrates feasibility in comparing mpMRI response, pathologic treatment response, and the underlying genomic features that drive tumor development versus treatment resistance. Clinical trial information: NCT02430480.