Background: Short-term antiandrogen (AA) flare protection is used to counter the testosterone surge associated with luteinising-hormone-releasing hormone (LHRH) agonist therapy. Degarelix, a gonadotrophin-releasing hormone antagonist, does not cause testosterone surge. Data from two phase III trials have been used to compare the one year efficacy of degarelix monotherapy versus combined agonist plus AA flare protection. Data has reported testosterone surge in agonist patients despite AA therapy, as well as improved prostate-specific antigen (PSA) progression-free survival (PFS) and lower mortality in degarelix patients. Here we focus on PSA PFS outcomes and serum alkaline phosphatase (S-ALP) in high risk patients (metastatic disease or PSA more than 50 ng/mL). Methods: Data were pooled from two randomised, one-year studies; CS21 compared monthly degarelix with leuprolide and CS35 compared 3 month formulations of degarelix and goserelin. AA was administered in the agonist groups at the investigator’s discretion. Analyses were performed by the Kaplan-Meier method and Log-rank test (probability of PSA PFS), Cox regression (adjusted hazard ratios [HR] for PSA PFS failure) and repeated measures ANCOVA (S-ALP). Results: Nine hundred seventy four patients received degarelix and 69 patients agonist plus AA. The agonist plus AA group contained a higher proportion of patients with Gleason score 7 to 10, metastatic disease, or baseline PSA more than 50 ng/mL compared with the degarelix group. Cox regression was used to account for these baseline differences. PSA PFS failure rate for metastatic patients and those with baseline PSA more than 50 ng/mL was significantly lower with degarelix than with agonist plus AA (HR=0.516, p=0.0198 and HR=0.490, p=0.0077, respectively). S-ALP levels in metastatic patients and those with baseline PSA more than 50 ng/mL during the year of treatment were significantly lower with degarelix (p=0.0025 and 0.0005, respectively). S-ALP fell below baseline by 2 months or less with degarelix and 7 months or less with agonist plus AA. Conclusions: This pooled analysis indicates LHRH agonist plus AA therapy flare protection may not achieve similar disease control as degarelix monotherapy during the first year of therapy in patients at high risk of symptomatic disease progression.