An emerging landscape for canonical and actionable molecular alterations in primary and metastatic prostate cancer.

Prostate cancer (PC) patients with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may impact treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic PC. Tumors from 1027 advanced PC patients that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27 gene panel) and co-occurring mutations in select canonical PC pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. MSI-H and TMB-H occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with anti-tumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1 and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA repair pathways, (2) intrinsic PC signaling pathways that may prevent anti-tumor immunity and (3) distinct genomic differences between localized and metastatic PC. These results lend support that genomic profiling for advanced PC may identify actionable targets not routinely used in the current metastatic paradigm.