title: Targeting DNA Repair: The Role of PARP Inhibition in the Treatment of Castration-Resistant Prostate Cancer.
abstract: Several genomic studies have identified DNA repair gene defects in prostate cancer in the last 5 years. The mechanisms by which these DNA repair defects promote carcinogenesis and tumor progression in the prostate have not been fully elucidated, but their presence in at least 20-25% of metastatic castration-resistant prostate cancers (CRPCs) provides an opportunity for a therapeutic strategy that turns a tumor strength into its weakness and may lead to arguably the first molecularly stratified treatment for this disease.Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed as an anticancer synthetic lethal therapeutic strategy for tumors with impaired homologous recombination DNA repair, based on a synthetic lethal effect. Poly(ADP-ribose) polymerase inhibitors have shown to induce significant tumor responses in cancer patients carrying germline BRCA1/2 mutations. Recent evidence from a phase II clinical trial supports further testing of PARP inhibitors for the treatment of metastatic CRPC with either germline or somatic defects in BRCA2, ATM, PALB2, and other DNA repair genes.We review the current evidence of how this strategy is relevant for the treatment of advanced prostate cancers, the available data from trials with PARP inhibitors in metastatic CRPC, and the ongoing studies analyzing combinations of these drugs with other therapies.
authors.affiliation: From the *Prostate Cancer Unit, Spanish National Cancer Research Centre (CNIO); and †HM Hospitales-Centro Integral Oncológico HM Clara Campal, Madrid, Spain; ‡Divisions of Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research; and §Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom; and ∥CNIO-IBIMA Genitourinary Cancer Unit at Hospital Virgen de la Victoria and Hospital Regional de Malaga, Malaga, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.forename: Joaquin
authors.initials: J
authors.lastname: Mateo
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D004260:DNA Repair; D006801:Humans; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors