AUA 2017: DNA Repair Defects in Prostate Cancer
Dr. Smith presented a case of a 54-year-old man with metastatic castration-resistant prostate cancer (mCRPC) who was initially diagnosed in 2008 with PC and underwent a laparoscopic prostatectomy for Gleason 4+5 disease, pT3bN0 adenocarcinoma. In 2010, his prostate-specific antigen was 2.2. Staging demonstrated retroperitoneal lymphadenopathy, so continual androgen deprivation therapy was started. In 2011, he progressed to CRPC, and since then has been on sequential treatment with sipuleucel-T, abiraterone acetate with prednisone, and subsequently with docetaxel. His family history was notable for his father being diagnosed at age 62 and succumbing to PC in his early 70s, so he was then referred for a genetics evaluation, which demonstrated pathogenic germline mutation for BRCA2. As Dr. Smith observed, the BRCA2 germline mutation in PC has revealed a heritable, particularly aggressive form of PC. BRCA2 alterations lead to defective DNA repair, transcription, and cell cycle regulation. As we know, germline BRCA2 mutations have historically been associated with breast and ovarian cancer and now, more recently, with PC and pancreatic cancer.
The mutational landscape for mCRPC specifically is quite burdensome, as a recent study noted that DNA repair alterations were found in 19.3% of these patients. Clinically, this has led to the development of poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib. PARP inhibitors specifically target strands of damaged DNA and lead to cellular apoptosis, which has demonstrated burden of disease regression. However, as Dr. Smith mentioned, future clinical trials that assess PARP inhibitors for PC need to answer the questions of (i) Which PARP inhibitors should we use? (ii) In which disease states should we employ them? (iii) Which biomarker should we utilize to assess eligibility and response? (iv) Which endpoints should we be assessing? One particular phase II study in this setting that is currently ongoing is the GALAHAD, a multicenter study for men with mCRPC and DNA repair anomalies.
Dr. Smith summarized his talk by noting that pathogenic germline mutations in DNA repair genes, as well as acquired DNA repair defects, are relatively common in metastatic PC. Preliminary evidence suggests that PARP inhibitors are active in treatment of refractory mCRPC. Dr. Smith’s recommendations were that patients should be considered for genetic counseling and testing if they are metastatic and/or have high-grade PC. Furthermore, individuals with treatment-refractory mCRPC should be considered for tumor genetic analyses and encouraged to participate in clinical trials.
Presented By: Matthew R. Smith, MD, PhD, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Twitter: @zklaassen_md
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA