Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities

Int J Mol Sci. 2024 Apr 24;25(9):4624. doi: 10.3390/ijms25094624.


More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Keywords: ATM; BRCA1; BRCA2; PARP inhibitor; androgen receptor; homologous recombination repair; metastatic prostate cancer.

Publication types

  • Review

MeSH terms

  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / genetics
  • Humans
  • Male
  • Neoplasm Metastasis
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / pathology
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Recombinational DNA Repair*


  • Poly(ADP-ribose) Polymerase Inhibitors
  • BRCA2 Protein
  • BRCA1 Protein
  • BRCA2 protein, human
  • Phthalazines
  • olaparib
  • Receptors, Androgen
  • BRCA1 protein, human
  • Piperazines

Grants and funding

This research received no external funding.