DNA Damage Response and Mismatch Repair Gene Defects in Advanced and Metastatic Prostate Cancer

Area of Science:

• Genetics and Genomics
• Oncology
• Molecular Biology

Background:

• Up to 25% of advanced prostate cancers (PCa) exhibit alterations in DNA damage response (DDR) and associated genes.
• Key affected pathways include homologous recombination repair, Fanconi anemia, and mismatch repair, leading to diverse DDR-deficient phenotypes.
• A significant proportion of these alterations involve non-BRCA DDR genes.

Purpose of the Study:

• To review the landscape of DDR alterations in advanced prostate cancer.
• To discuss the therapeutic implications of these alterations, particularly focusing on targeted therapies.
• To identify current challenges and future directions in treating DDR-deficient prostate cancer.

Main Methods:

• Literature review of studies investigating DDR gene alterations in prostate cancer.
• Analysis of clinical trial data for therapies targeting DDR-deficient tumors.
• Synthesis of information on the efficacy of various targeted agents, including PARP inhibitors, immune checkpoint inhibitors, and ATR inhibitors.

Main Results:

• Poly-ADP-ribose polymerase (PARP) inhibitors show efficacy in prostate cancer with BRCA1/BRCA2 alterations.
• Mismatch repair-deficient PCa and a subset of CDK12-deficient PCa are responsive to immune checkpoint inhibitors.
• ATR inhibitors show emerging efficacy in PCa with ATM deficiencies.

Conclusions:

• While targeted therapies exist for certain DDR-deficient prostate cancers (e.g., PARP inhibitors for BRCA mutations), many non-BRCA DDR alterations lack established treatment options.
• Further research is needed to clarify the therapeutic implications of the heterogeneous spectrum of DDR alterations in PCa.
• Developing novel targeted treatments for the broader range of DDR-deficient prostate cancers remains a critical unmet need.