Daniel P. Petrylak, MD, presented “The Role of Targeting DNA Repair Mutations in Advanced Prostate Cancer with PARP Inhibitors” during the 19th Annual Future Directions in Urology Symposium on August 11, 2018 in Colorado Springs, Colorado.
How to cite: Petrylak, Daniel P.. “The Role of Targeting DNA Repair Mutations in Advanced Prostate Cancer with PARP Inhibitors” August 11, 2018. Accessed [date today]. https://grandroundsinurology.com/controversies-in-renal-cell-carcinoma-adjuvant-tkis-and-clinical-trial-updates/
The Role of Targeting DNA Repair Mutations in Advanced Prostate Cancer with PARP Inhibitors – Summary:
Daniel P. Petrylak, MD, provides a brief update on clinical trials evaluating therapies that target DNA repair mutations in castration resistant prostate cancer (CRPC) patients, including poly (ADP-ribose) polymerase (PARP) inhibitors, agents that exploit hypoxia-inducing BRCAness, and next generation anti-androgens.
PARP Inhibitors for CRPC Patients with DNA Repair Mutations
A summary of studies from seven different institutions shows that DNA repair mutations express in about 12% of CRPC patients.
The TOPARP trial observed olaparib in CRPC patients with and without DNA repair mutations. Those patients with DNA repair mutations had a much higher response rate compared to those who did not. Furthermore, there are phase III trials currently evaluating PARP inhibitors, including olaparib, rucaparib, and veliparib.
Understanding drug responses in patients with DNA repair mutations is essential for therapeutic layering in prostate cancer.
Hypoxia-Induced BRCAness in Prostate Cancer
Because about 12% of CRPC patients have BRCA mutations, methods to use DNA repair mutations to cause cancer cell death are under evaluation. Dr. Petrylak’s junior attending physician, Joseph Kim, MD, is currently leading a randomized phase II trial comparing olaparib alone to an olaparib/cediranib combination to exploit hypoxia-inducing BRCAness. Patients in the olaparib alone arm who progress are eligible to receive cediranib. Hopefully, this combination therapy does induce BRCAness in these patients.
Next Generation Anti-androgens
Next generation anti-androgens can also benefit CRPC patients with DNA repair mutations. Preclinical data shows that abiraterone will increase or decrease DNA repair enzymes. A phase II study comparing veliparib with abiraterone to abiraterone alone show superior progression-free survival (PFS) with the combination. This study is expanding to a phase III trial in order to test the particular hypothesis. Additionally, there is a possibility that patients who do not have DNA repair mutations will respond to this combination. Appropriate patient selection is imperative when utilizing this combination, due to cardiovascular toxicity seen in this study. However, this is an exciting finding that needs further confirmation.
About Dr. Petrylak
Dr. Petrylak is the Professor of Urology and Medicine at the Smilow Cancer Hospital at Yale University. He has expertise in the research and development of new drugs and treatments, especially immunotherapies and checkpoint inhibitors, to fight prostate cancer.
About the Future Directions in Urology Symposium
The Future Directions in Urology Symposium (FDUS) is an annual collaborative meeting with a faculty consisting of the top researchers, physicians, and educators in the field of urology. During FDUS, experts provide updates on recent developments and debate innovative management approaches in genitourinary cancers and urologic conditions. Subsequently, the experts devise consensus statements in accordance with the discussions held in the meeting.
In this video, Dr. Petrylak discloses the thesis of the discussion he led during FDUS.
ABOUT THE AUTHOR
Daniel P. Petrylak, MD, leads the genitourinary cancers medical oncology team at Smilow Cancer Hospital as director of the genitourinary cancer research group, professor, and co-director of the Cancer Signaling Network program. Dr. Petrylak joined Yale from Herbert Irving Cancer Center at Columbia University Medical Center with New York-Presbyterian Hospital, where he served as Professor of Medicine (Medical Oncology) and Urology and began his appointment in September of 2012. Dr. Petrylak is a member of the American Association for Cancer Research (AACR), American Society for Clinical Oncology (ASCO), American College of Physicians (ACP), American Association for the Advancement of Science (AAAS), American Urological Association (AUA), and the Southwest Oncology Group (SWOG). After serving for more than 20 years as the advanced bladder chair for SWOG, Dr. Petrylak is now the Vice Chair of the Genitourinary Committee. He additionally has led multiple national and international studies in prostate and bladder cancer.
Dr. Petrylak’s research interests span both prostate and bladder cancer. He led an investigator-initiated trial of docetaxel and estramustine in castration resistant prostate cancer. The results of this study supported a phase 3 trial of this combination in SWOG led by Dr. Petrylak, which in turn, supported the FDA approval of docetaxel for castration resistant prostate cancer. This was one of the first two trials to demonstrate a survival benefit in this state of disease. Dr. Petrylak has also been instrumental in the development of immunotherapy and targeted therapies for refractory bladder cancer. His work with Enfortumab Vedotin has supported the accelerated and full FDA approval of this drug.
Dr. Petrylak received his undergraduate degree from Columbia College and his medical degree from Case Western University School of Medicine. He completed his internship and residency at Albert Einstein College of Medicine and his fellowship in medical oncology at Memorial Sloan-Kettering Cancer Center. He has authored more than 200 peer-reviewed articles and book chapters on prostate and bladder cancer research outcomes.
