Related Experiment Video
Updated: Aug 23, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate
Zachary Quinn1, Benjamin Leiby1, Guru Sonpavde2
1Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
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.
Insights
This study found that combining niraparib (a PARP inhibitor) with Radium-223 is safe for treating metastatic castrate-resistant prostate cancer. Further research with biomarkers is recommended to optimize this combination therapy.
Area of Science:
- Oncology
- Radiopharmaceutical Therapy
- Molecular Targeted Therapy
Background:
- Metastatic castrate-resistant prostate cancer (mCRPC) remains a significant clinical challenge.
- PARP inhibitors and Radium-223 are emerging therapeutic agents for advanced prostate cancer.
- Identifying safe and effective combination strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the safety and determine the maximum tolerated dose (MTD) of niraparib in combination with Radium-223.
- To assess the safety profile of this combination in men with mCRPC lacking BRCA mutations.
- To explore preliminary efficacy and predictive biomarkers for response.
Main Methods:
- A dose-escalation study using a time-to-event continual reassessment method was conducted.
- Thirty patients with progressive mCRPC received escalating doses of niraparib with standard Radium-223.
- Safety endpoints included dose-limiting toxicities (DLTs), and secondary endpoints included PSA response and progression-free survival.
Main Results:
- The MTD of niraparib was determined to be 100 mg for patients with prior chemotherapy and 200 mg for chemotherapy-naïve patients.
- Common adverse events included neutropenia and thrombocytopenia; fatigue and nausea were also reported.
- Exploratory analyses identified differential gene expression patterns in responders versus nonresponders.
Conclusions:
- The combination of niraparib and Radium-223 demonstrates an acceptable safety profile in patients with mCRPC.
- Further investigation incorporating biomarkers is warranted to optimize the use of PARP inhibitors with DNA damaging agents.
- This combination therapy holds potential for managing advanced prostate cancer, pending biomarker-guided selection.
