San Francisco, CA USA (UroToday.com) Dr. De Bono gave an overview on the role of DNA repair as a novel target in treatment of metastatic Castrate-Resistant Prostate Cancer (mCRPC). mCRPC is a highly heterogeneous disease. 20-30% of mCRPC have a defect in DNA repair machinery involving genes such as BRCA2. Up to 50% of these are in germline DNA, which are heritable. There is recently increasing evidence that DNA repair defects lead to much worse prognosis.
DNA repair defects can be targeted successfully with PARP inhibitors or platinum. However, PARP inhibitors are currently approved in Ovarian Cancer and not in Prostate Cancer. PARP inhibitors can be selective against prostate cancer cells, which have DNA repair defects making them vulnerable to therapeutic strategies utilizing PARP inhibition. As such, these drugs may have limited systemic toxicity.
Dr. De Bono then discussed Phase II trial (NCT01682772), which uses PARP inhibitor Olaparib 400mg BID among patients with mCRPC. The goal of the study is to evaluate the anti-tumor activity of Olaparaib as well as identify clinical biomarkers to stratify patients who will response to Olaparib. The study mandated pre- and post-PARP inhibitor tumor biopsies to identify biomarkers.
The study accrued 50 mCRPC patients. These patients have had 1-2 prior taxane chemotherapy. They have had documented progressive disease by RECIST. Baseline CTC count was 37, which makes these very advanced diseases. Despite having had multiple approved therapies (docetaxel, enzalutamide, abiraterone), these patients responded well. Almost all patients have had CTC decline. Several patients have had radiographic responses.
Almost all responders have had DNA repair defects. The group used a series of DNA repair defect panel to test them as a biomarker. This returned a sensitivity of 87.5% and specificity 93.5%. Two main biomarkers were identified, including BRCA2loss and ATM defects. Overall survival and progression free survival was significantly better in patients with a positive biomarker.
PARP inhibitors may be a promising therapeutic in up to 20-30% of mCRPC patients who may have actionable DNA repair defects.
Presented By:
Johann S. De Bono, MD, MSc, PhD, FRCP, FMedSci, MB ChB
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Reported By:
Mohammed Haseebuddin, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA