Treatment strategies for DNA repair-deficient prostate cancer

Abstract

Introduction: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas Covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert Commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer treatment in the coming years. Work is needed to define the optimal tissue to test, and to define the national history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with ‘actionable’ mutations are now needed.

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer

“…The current study, coupled with our secondary analysis of the StandUp2Cancer dataset, suggests that DNA-repair defects (DRD) may be further enriched in AR-V7-positive prostate cancers with a prevalence approaching 40%. These DRD+ patients may benefit from alternative treatment strategies including poly–ADP-ribose polymerase (PARP) inhibitors [ 22 ] or other genetically-targeted approaches [ 23 , 24 ]. The potential association between AR-V7 detection and DRD mutations has also been suggested by a previous study,[ 14 ] but still requires further confirmation.…”

Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

“…The population positive-predictive value and population negative-predicative value were calculated based on an estimate of a 10% prevalence of any DNA repair gene mutations and a 6% prevalence of BRCA1/2 and ATM mutations specifically. 20 The combination with the highest positive-predictive value was chosen as the optimal enrichment threshold. Analyses were performed using R version 3.4.4.…”

PARP inhibitors for homologous recombination-deficient prostate cancer

“…[77] For example, it is not currently known whether particular HR defects may demonstrate different sensitivities to PARP inhibitors, since some HR genes may be more redundant than others. It is possible, for instance, that only patients with BRCA2 and ATM mutations will respond most favorably to PARP inhibitors while other HR gene mutations might not be associated with the same degree of synthetic lethality.…”