Multicenter phase 2 trial of radium-223 with or without olaparib for castration-resistant prostate cancer with bone metastases

Radium-223 therapy improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between PARP inhibition and radiation. The multicenter randomized phase 2 COMRADE trial in the USA evaluated addition of olaparib to radium-223 in men with mCRPC with bone metastases (BMs). Men with mCRPC and two or more BMs were randomized 1:1 to olaparib 200 mg twice daily plus radium-223 (intravenous 55 kBq/kg every 4 weeks x 6 doses) or radium-223 alone. Crossover was allowed at progression. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS). Among 120 randomized patients, 96% had previously received androgen receptor pathway inhibitor, 52% had received docetaxel, 47% had more than 20 BMs, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 versus 4.7 months; HR 0.50; p=0.0042). The benefit was most pronounced in patients without prior docetaxel (13.7 versus 5.7 months; HR 0.24; 90% CI 0.15-0.40) and those with 20 or less BMs (13.4 versus 4.2 months; HR 0.21; 90% CI 0.13-0.33). The cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% versus 22.9% at one year). Median overall survival was similar (20.2 versus 21.1 months). Grade 3 or higher treatment-related adverse events occurred in 56% of patients with the combination versus 33% of patients with radium-223 alone. The authors conclude that addition of olaparib to radium-223 was associated with significantly prolonged rPFS in mens with mCRPC and BMs.