Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Purpose: 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. Patients and Methods: 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. Results: Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas 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, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders. Conclusions: 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.

Original languageEnglish
Pages (from-to)50-59
Number of pages10
JournalClinical Cancer Research
Issue number1
StatePublished - Jan 1 2023

Bibliographical note

Funding Information:
The authors would like to thank Ms. Deborah Della Manna and Dr. Jianqing Zhang for performing the NanoString experiments. In addition, we thank Jake Vinson, Garrett Abrams, Sarah Wise, and other members of the Prostate Cancer Clinical Trials Consortium for their ongoing support.

Publisher Copyright:
© 2022 American Association for Cancer Research.

ASJC Scopus subject areas

  • Medicine (all)


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