ASCO 2017: Targeting DNA Repair Mutations in Metastatic Castration-Resistant Prostate Cancer

Chicago, IL ( Dr. Johann De Bono from London, UK presented the final talk of the “How to Integrate Multimodal Therapy Into the Management of Castration-Resistant Prostate Cancer (CRPC)” at the 2017 ASCO annual meeting session. His presentation was assessing DNA repair mutations among men with CRPC.

Dr. De Bono started his talk by posing 3 questions to the audience, highlighting a few important points: (i) germline deleterious BRCA mutation carriers with prostate cancer have a poor prognosis, (ii) BRCA1 deleterious aberrations are much less common than BRCA2 aberrations in metastatic prostate cancer, and (iii) deleterious BRCA2 mutations are not necessarily associated with resistance to abiraterone and enzalutamide.

Subsequently, Dr. De Bono made an urgent plea that we need to individually stratify our patient treatment, considering that what we have is not good enough, our patients are still dying, most phase III trials fail, our treatments only work for a subset of patients, and the emerging biology tells us that we must stratify. At the crux of this argument is that prostate cancer is a highly heterogeneous group of diseases, with both inter-patient and intra-patient heterogeneity. This is secondary to many different genomic aberrations, specifically DNA repair defects which encompasses mismatch repair (MMR) defects and homologous recombination (HR) repair defects. Based on work at Dr. De Bono’s Royal Marsden Hospital, we know that only 5-8% of mCRPC patients have MMR defects, often with a relatively low mutational load. This has led to further research identifying a certain degree of PD-L1 expression in MMR defective tumors. The recently published TOPARP-A Trial demonstrated that patients with mCRPC unresponsive to standard therapy who had DNA-repair defects responded to the PARP inhibitor olaparib [1]. Specifically, 16 of 49 patients (33%) had a response to olaparib, with 12 patients remaining on treatment for >6 months. Germline mutations have also been extensively studied in the prostate cancer arena. Among >700 patients with mCRPC who have had their germline DNA sequenced, >10% of patients have germline aberrations of DNA repair genes.

In conclusion, Dr. De Bono highlights a number of practical take-home points: (i) treatment molecular stratification of prostate cancer has arrived, specifically with immune therapy treatment in patients with certain MMR defective genes and PARP inhibitors for those with HR DNA repair defective disease, (ii) analytically validated biomarkers should become widely available to drive stratified clinical trial accrual, and (iii) completing key clinical trials will be necessary, noting that 4 registered trials are currently ongoing. 

Presented By: Johann S. De Bono, The Institute of Cancer Research and The Royal Marsden Hospital, London, UK

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre 
Twitter: @zklaassen_md 

1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015 Oct 29;373(18):1697-1708.

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA