European Urology: Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide

Emmanuel S.Antonarakisab†, ChangxueLub†  BrandonLubera  ChaoLiangb  HaoWanga  YanChenb  John L.Silbersteinb DaniloPianab ZhaoLaic YidongChencd William B.Isaacsab JunLuoab

Abstract

Background

Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.

Objective

To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.

Design, setting, and participants

We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.

Outcome measurements and statistical analysis

We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.

Results and limitations

Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations.

Conclusions

Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.

Patient summary

Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

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