Background: Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are at high risk of developing metastatic CRPC. In the primary analysis of PROSPER, enzalutamide (ENZA) provided a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) in men with nmCRPC. Here we report the impact of prior therapy on MFS. Methods: Eligible men with nmCRPC, prostate-specific antigen (PSA) doubling time ≤ 10 months, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy and were randomized 2:1 to ENZA 160 mg or placebo (PBO). The primary endpoint was MFS. Results: 1401 men were enrolled, with a median age of 74 y (range, 50-95 y). In all men, ENZA reduced the risk of metastasis or death by 71% (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24-0.35; P< .0001). The treatment effect consistently favored ENZA regardless of whether men had prior bilateral orchiectomy, prior radiation, ≤1 or > 1 prior hormonal therapy, or prior bone-targeting therapy (Table). Men who received > 1 prior hormonal therapy had a shorter median MFS than those who received ≤1 line of hormonal therapy (5 months and 3 months in the ENZA and PBO groups, respectively). Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful reduction in the risk of developing metastases or death irrespective of prior surgery, radiation, or bone-targeting therapy. MFS was longer in men who had received ≤1 prior hormonal therapy. Clinical trial information: NCT02003924

Abbreviation: NR, not reached.