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

Eur Urol. 2018 Aug;74(2):218-225. doi: 10.1016/j.eururo.2018.01.035. Epub 2018 Feb 10.

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.

Keywords: Abiraterone; DNA repair; Enzalutamide; Germline; Mutation.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Androgen Antagonists / administration & dosage*
  • Androgen Antagonists / adverse effects
  • Androstenes / administration & dosage*
  • Androstenes / adverse effects
  • Antigens, Neoplasm / blood
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Benzamides
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics*
  • Clinical Decision-Making
  • DNA Mutational Analysis
  • DNA Repair Enzymes / genetics*
  • GPI-Linked Proteins / blood
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Proteins / blood
  • Nitriles
  • Phenotype
  • Phenylthiohydantoin / administration & dosage
  • Phenylthiohydantoin / adverse effects
  • Phenylthiohydantoin / analogs & derivatives*
  • Precision Medicine
  • Progression-Free Survival
  • Prospective Studies
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Time Factors
  • Treatment Outcome

Substances

  • Androgen Antagonists
  • Androstenes
  • Antigens, Neoplasm
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Benzamides
  • Biomarkers, Tumor
  • GPI-Linked Proteins
  • Neoplasm Proteins
  • Nitriles
  • PSCA protein, human
  • Phenylthiohydantoin
  • enzalutamide
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA Repair Enzymes
  • abiraterone