Daniel P. Petrylak, MD, presented “PARP in Combination with Standard-of-Care Treatment” during the 3rd Annual International Prostate Cancer Update on January 26, 2019 in Beaver Creek, Colorado.
How to cite: Petrylak, Daniel P. “PARP in Combination with Standard-of-Care Treatment” January 26, 2019. Accessed Jul 2024. https://grandroundsinurology.com/parp-in-combination-with-standard-of-care-treatment/
PARP in Combination with Standard-of-Care Treatment
Daniel P. Petrylak, MD, discusses the potential role of PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) treatment. He also discusses the two methods for approaching combination therapy with PARP inhibitors: hypoxia and the anti-androgen blockade.
PARP Inhibitors for mCRPC
Doctors first used PARP inhibitors, a class of drugs targeting poly ADP ribose polymerase (PARP), as a treatment option in cancers like ovarian cancer. However, results from the TOPARP study suggested that PARP inhibitors are active in prostate cancer as well.
This study looked at 49 patients with metastatic castration resistant prostate cancer (mCRPC) who were docetaxel pretreated. Of the 16 patients who had mutations in the DNA repair pathway, 14 responded to PARP inhibition treatment, whereas only 2 patients out of 33 responded in the group without DNA repair mutations.
Since the TOPARP study, several more studies have begun investigating PARP inhibition in patients with mCRPC. Some PARP inhibitors under investigation as single agent treatments include olaparib, rucaparib, and niraparib.
Combination Therapy
Combination PARP inhibitor therapy may give patients a better chance of responding than monotherapy. The two methods for approaching combination therapy are hypoxia and the anti-androgen blockade. For example, cediranib is an agent that induces hypoxia. Cediranib is an anti-angiogenesis agent that effects VEGFR-1/2 and decreases angiogenesis, vascular permeability, and the survival of new blood cells. Researchers at Yale University are investigating cediranib in combination with olaparib. The belief is that this combination will have a higher response rate (RR) and progression free survival (PFS) than olaparib alone in mCRPC patients.
On the other hand, combining PARP inhibitors with anti-androgens may be a viable combination. Anti-androgens are thought to enhance the blockade of androgen synthesis and increase BRACness. The phase II NCI 9012 study is investigating the combination of abiraterone acetate and veliparib. Overall, in the study so far, there have been no significant differences in PSA decline or PFS. Therefore, this study has not met its primary endpoint. Notably, there has been a higher RR in patients with DNA repair enzyme mutations than those without.
Results of another phase II trial, which compared olaparib in combination with abiraterone to abiraterone monotherapy in patients with previously treated mCRPC, showed about a 5.6 month increase in PFS in the combination arm. However, a difference in overall survival (OS) is not apparent at this point in the study. Consistent with results from other studies, about 15% of patients in this trial had DNA repair mutations. Promisingly, there does seem to be a difference in favor of the combination in patients with DNA repair mutations. Other trials involving checkpoint inhibitors and PARP inhibitors show that there seems to be activity in this combination. For instance, even patients without DNA repair mutations are responding to the combination of pembrolizumab and olaparib.
Conclusions
PARP inhibitors do have activity in patients with aberrant DNA repair pathways. Many combination studies are investigating inducing BRACness to improve efficacy of PARP inhibitors in patients without DNA repair mutations.
About the International Prostate Cancer Update
The International Prostate Cancer Update (IPCU) is an annual, multi-day CME conference focused on prostate cancer treatment updates. The conference’s faculty consists of international experts, and the event caters to urologists, medical oncologists, radiation oncologists, and other healthcare professionals. Topics encompass prostate cancer management, from diagnosis to treating advanced and metastatic disease. Dr. Petrylak presented this lecture during the 29th IPCU in 2019. Please visit this page in order to learn more about future IPCU meetings.
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.
