Molecular testing of DNA damage response pathways in prostate cancer patients.

PURPOSE OF REVIEW: Personalizing prostate cancer therapy requires germline and tumor molecular tests that predict who will respond to specific treatments and who may not. The review covers molecular testing of DNA damage response pathways, the first biomarker-driven precision target with clinical utility for treatment selection in patients with castration resistant prostate cancer (CRPC).

RECENT FINDINGS: Recurrent somatic and germline variants cause deficiency of the mismatch repair (MMR) or homologous recombination (HR) pathways in about a quarter of CRPC patients. In prospective clinical trials, patients with deleterious variants in the MMR pathway more frequently experience a therapeutic response to immune checkpoint inhibitors (ICI). Similarly, somatic and germline events affecting HR predict response to poly(ADP) ribose polymerase inhibitor (PARPi) therapy. Molecular testing of these pathways currently involves assaying for loss of function variants in individual genes and for the genome-wide consequences of repair deficiency.

SUMMARY: DNA damage response pathways are the first major area of molecular genetic testing in CRPC settings and offer insights into this new paradigm. Our hope is that eventually an arsenal of molecularly-guided therapies will be developed across many pathways to enable precision medicine options for most men with prostate cancer.