Genomic Biomarkers and Genome-Wide Loss-of-Heterozygosity Scores in Metastatic Prostate Cancer Following Progression on Androgen-Targeting Therapies.

Abstract

To study the impact of standard-of-care hormonal therapies on metastatic prostate cancer (mPC) clinical genomic profiles in real-world practice, with a focus on homologous recombination-repair (HRR) genes. Targeted next-generation sequencing of 1,302 patients with mPC was pursued using the FoundationOne or FoundationOne CDx assays. Longitudinal clinical data for correlative analysis were curated via technology-enabled abstraction of electronic health records. Genomic biomarkers, including individual gene aberrations and genome-wide loss-of-heterozygosity (gLOH) scores, were compared according to biopsy location and time of sample acquisition (androgen deprivation therapy [ADT]-naïve, ADT-progression and post-ADT, and novel hormonal therapies [NHT]-progression), using chi-square and Wilcoxon rank-sum tests. Multivariable analysis used linear regression. False-discovery rate of 0.05 was applied to account for multiple comparisons. Eight hundred forty (65%), 132 (10%), and 330 (25%) biopsies were ADT-naïve, ADT-progression, and NHT-progression, respectively. Later-stage samples were enriched for <i>AR</i>, <i>MYC</i>, <i>TP53</i>, <i>PTEN</i>, and <i>RB1</i> aberrations (all adjusted <i>P</i> values < .05), but prevalence of HRR-related <i>BRCA2</i>, <i>ATM</i>, and <i>CDK12</i> aberrations remained stable. Primary and metastatic ADT-naïve biopsies presented similar prevalence of <i>TP53</i> (36% <i>v</i> 31%) and <i>BRCA2</i> (8% <i>v</i> 7%) aberrations; 81% of ADT-naïve <i>BRCA2</i>-mutated samples presented <i>BRCA2</i> biallelic loss. Higher gLOH scores were independently associated with HRR genes (<i>BRCA2</i>, <i>PALB2</i>, and <i>FANCA</i>), <i>TP53</i>, and <i>RB1</i> aberrations, and with prior exposure to hormonal therapies in multivariable analysis. Prevalence of HRR-gene aberrations remains stable along mPC progression, supporting the use of diagnostic biopsies to guide poly (ADP-ribose) polymerase inhibitor treatment in metastatic castration-resistant prostate cancer. gLOH scores increase with emerging resistance to hormonal therapies, independently of individual HRR gene mutations.