Background: Low-toxicity therapies for LT tmt of mCRPC pts is an unmet need. The final analysis of the COU-AA-302 study (302) (median follow-up: 4.1 yrs) showed that AA + P significantly improves overall survival (OS) and has a favorable safety profile in chemo-naïve mCRPC pts. We assessed the LT safety of AA + P in pts treated for ≥ 4 and < 4 yrs in 302. Methods: 302 was an international phase 3, double-blind study of chemo-naïve mCRPC pts randomized 1:1 to AA 1000 mg + P 5 mg po BID (n = 546) vs placebo + P (n = 542). A post hoc analysis of adverse events (AEs) and an efficacy analysis were performed for pts with ≥ 4 (n = 41) and < 4 (n = 501) yrs of tmt with AA + P. Results: Baseline characteristics were similar for the ≥ 4 and < 4 yrs groups, with the exception of median age (67 and 71 yrs) and time from androgen deprivation to first AA + P dose (56 and 39 months [mos]), respectively. Median tmt duration was 50 mos in the ≥ 4 yrs group and 13 mos in the < 4 yrs group. The frequency of any grade and grade 3/4 AEs was similar for the ≥ 4 and < 4 yrs groups. The most common AEs were fatigue, diarrhea, arthralgia, back pain, and edema peripheral. The majority were grade 1/2 (Table). No pts in the ≥ 4 yrs group had an AE leading to tmt discontinuation, and 50 pts in the < 4 yrs group discontinued due to AEs. No pt in the ≥ 4 yrs group had died at the time of analysis. As expected, median time to prostate-specific antigen (PSA) progression was longer (47 vs 9 mos) and PSA response rate was greater (98% vs 66%) in the ≥ 4 vs < 4 yrs groups, respectively. Conclusions: 41 of 546 pts continued LT AA + P (≥ 4 yrs), and no new safety signals were associated with prolonged treatment with AA + P. Pts on LT AA + P may progress but have excellent survival and manageable toxicity.