Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Genomic instability is a key feature of cancer, with homologous recombination repair gene alterations common in prostate cancer (PCa).
• Approximately 20% of PCa cases involve defects in DNA repair genes, including BRCA2, BRCA1, ATM, and CHEK2, leading to a 'BRCAness' phenotype.
• Poly(ADP-ribose) polymerase inhibitors (PARPis) exploit synthetic lethality in cancers with impaired homologous recombination repair.

Purpose of the Study:

• To review the molecular mechanisms of PARPis in prostate cancer.
• To summarize preclinical and clinical data on PARPis for PCa treatment.
• To highlight the potential of PARPis in conjunction with androgen deprivation therapy.

Main Methods:

• Review of existing scientific literature on PARPis, genomic instability, and prostate cancer.
• Analysis of data from clinical trials, including the PROFOUND phase III trial.
• Examination of molecular mechanisms underlying PARPi efficacy and interaction with androgen signaling.

Main Results:

• PARPis demonstrate clinical efficacy in various cancers, including a subset of PCa.
• The PROFOUND trial showed improved radiological progression-free survival (rPFS) and overall survival (OS) with olaparib in mCRPC patients harboring BRCA1, BRCA2, or ATM mutations.
• PARPis can reduce androgen signaling through interactions with the androgen nuclear complex.

Conclusions:

• PARPi therapy is a promising targeted treatment for prostate cancer patients with specific DNA repair gene alterations.
• Molecular tumor boards are increasingly important for personalized oncological approaches in PCa.
• Further research and clinical application of PARPis in PCa are warranted.