Therapeutic Implications of DNA repair defects in Metastatic Prostate Cancer

Johann de Bono1,2

1The Institute of Cancer Research, London, UK,2Royal Marsden, London, UK

Abstract

 

Metastatic prostate cancer is a highly heterogeneous disease; Donald Gleason captured this heterogeneity in his pathological grading system, recognizing both intra-patient and inter-patient heterogeneity. Despite this our treatment for this disease has not to date pursued any molecular stratification. We hypothesized that a subset of poor prognosis prostate cancers had DNA repair defects and that these would sensitize to PARP inhibition. Preliminary data indicate that BRCA mutation carriers who suffered prostate cancers have poorer prognosis disease and are sensitive to PARP inhibition. We have also published that PARP inhibitors have some antitumour activity in this disease, with previous studies indicating that platinums including satraplatin also resulting in a 20-30% response rate. We therefore conducted an investigator initiated, adaptive, multi-step Phase II trial (TOPARP) of olaparib in patients with advanced prostate cancer. TOPARP-A is now completed and has demonstrated antitumour activity in heavily pretreated patients with metastatic castration resistant prostate cancer (CRPC) with responses being associated with molecular aberrations in DNA repair genes including BRCA2, ATM, PALB2 and other genes critical to DNA repair. These data indicate that this inter-patient genomic divergence may lead to phenotypic convergence. The response data, and predictive biomarker qualification data will be presented. These data may support for the first time molecular stratified treatment for this common cancer.