To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate resistant prostate cancer (mCRPC) in men without known BRCA mutations.
Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability < 20% was defined as MTD. Secondary endpoints included PSA change and progression free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples.
Thirty patients were treated with niraparib and radium-223: 13 patients received 100mg, 12 received 200mg and 5 patients received 300mg of niraparib. There were 6 DLT events: 2(13%) for neutropenia, 2(13%) for thrombocytopenia, while fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, while the MTD for chemotherapy naïve patients was 200mg. Whole blood gene expression of PAX5 and CD19 were higher in responders and ARG-1, IL-2R and FLT3 expression were higher in non-responders.
Combining niraparib with Radium-223 in patients with mCRPC was safe however further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Nov 02 [Epub ahead of print]
Zachary Quinn, Benjamin Leiby, Guru Sonpavde, Atish D Choudhury, Christopher Sweeney, David Einstein, Russell Szmulewitz, Oliver Sartor, Karen Knudsen, Eddy Shih-Hsin Yang, Wm Kevin Kelly
Thomas Jefferson University, Philadelphia, PA, United States., Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, United States., AdventHealth Cancer Institute, Orlando, FL, United States., Dana-Farber Cancer Institute, Boston, MA, United States., Beth Israel Deaconess Medical Center, Boston, United States., University of Chicago, Chicago, IL, United States., Tulane University School of Medicine, New Orleans, LA, United States., Sidney Kimmel Cancer Center at Jefferson Health, Philadelphia, PA, United States., University of Alabama at Birmingham, Birmingham, AL, United States., Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA, United States.