Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223.
Men with mCRPC and ≥2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS).
A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%).
Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2026 May 07 [Epub ahead of print]
Rana R McKay, Wanling Xie, Archana Ajmera, Arlene Araneta, Christina Jamieson, Edmund Folefac, Arif Hussain, Christos E Kyriakopoulos, Danielle K Manning, Adam Olson, Mamta Parikh, Rahul Parikh, Biren Saraiya, Lincoln W Pasquina, Russell Madison, Sarah Clifford, Merrida Childress, Amaya Gasco, Percy Ivy, Eliezer Van Allen, Bose Kochupurakkal, Geoffrey I Shapiro
University of California San Diego, La Jolla, CA., Dana-Farber Cancer Institute, Boston, MA., Ohio State University, Columbus, OH., University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD., University of Wisconsin, Madison, WI., Brigham and Women's Hospital, Boston, MA., University of Pittsburgh Medical Center, Pittsburgh, PA., University of California Davis, Sacramento, CA., University of Kansas Medical Center, Kansas City, KS., Rutgers Cancer Institute of New Jersey, New Brunswick, NJ., Foundation Medicine, Boston, MA., National Cancer Institute at the National Institutes of Health, Rockville, MD.