Multicenter, Randomized, Phase II Trial of Olaparib Plus Radium-223 Versus Radium-223 in Men With Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)

Abstract

PURPOSE 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. PATIENTS AND METHODS 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). RESULTS 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%). CONCLUSION 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.