Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial.

Abstract

The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to <i>PTEN</i> copy-number loss (34%) and/or activating mutations in <i>PIK3</i> genes or <i>AKT</i> (18%) and <i>TP53</i> mutation or loss in 33%. No androgen receptor (<i>AR</i>) aberrations were detected; <i>RB1</i> loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). <i>BRCA2</i> mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% <i>v</i> 15%), Wnt pathway (16% <i>v</i> 4%), and chromatin remodeling (16% <i>v</i> 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences (<i>AR</i>, <i>RB1</i>). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.