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

Purpose: 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.

Patients And Methods: 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.

Results: 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 , , , , and aberrations (all adjusted values < .05), but prevalence of HRR-related , , and aberrations remained stable. Primary and metastatic ADT-naïve biopsies presented similar prevalence of (36% 31%) and (8% 7%) aberrations; 81% of ADT-naïve -mutated samples presented biallelic loss. Higher gLOH scores were independently associated with HRR genes (, , and ), , and aberrations, and with prior exposure to hormonal therapies in multivariable analysis.

Conclusion: 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.