Background: The optimal approach to PC patients (pts) who biochemically relapse following a radical prostatectomy (RP) is not known. Pts with a rapidly rising PSA are at high risk of early metastasis and death. We conducted a phase III study in such pts to determine the clinical benefit of adding chemotherapy to early hormonal therapy (ADT). All pts have been treated. Here we report the safety results. Methods: Pts with PC who underwent a RP ± salvage RT and developed a rising PSA with a doubling time ≤ 9 months (mo) and no evidence of metastasis were eligible. PSA ≥ 1 ng/mL and testosterone (T) ≥ 100 ng/dl were required. Prior ADT ≤ 6 mo was allowed. Pts were randomized (1:1) to receive L 22.5 mg q3 mo x 18 mo, bicalutamide 50 mg x 30 days, with (Arm A) or without (Arm B) D 75 mg/m2 q3 weeks x 10 cycles. The primary endpoint was PFS at 18 mo post treatment (tx), with T recovery > 50 ng/dl. A sample size of 412 was calculated to detect a HR of 1.6 with 90% power. Results: 400 pts received tx (Arm A = 196, Arm B = 204) and 352 pts completed tx (Arm A = 170, Arm B = 182). 87% of pts treated in Arm A and 89% of pts treated in Arm B completed tx. Pts in Arm A received a mean of 9 cycles of D (range: 1-10), with 79.1% receiving all cycles. Pt compliance for L and bicalutamide was 100%. A greater % of Arm A pts experienced tx-related adverse events (AEs) (93.9 vs. 66.7%), AEs ≥ Gr 3 (48 vs. 10.8%), and serious AEs (25 vs. 9.8%). Most common AEs in Arm A were alopecia (Gr 1-2), fatigue, hot flush, edema, and diarrhea (Gr 1-4), and in Arm B were hot flush (Gr 1-4) and fatigue (Gr 1-2). Most common Gr ≥ 3 AEs in Arm A were neutropenia (15.8%), febrile neutropenia (6.6%), fatigue (4.6%), hyperglycemia (2.6%), and peripheral neuropathy (2.0%). In Arm B, no AE of Gr ≥ 3 occurred in more than 1 pt. Conclusions: ADT for 18 mo ± D for 10 cycles is feasible when given to pre-metastatic castration-sensitive PC pts. As expected, tx in Arm A was concordant with the known D safety profile. Collection of data for analysis of the primary endpoint is ongoing. Clinical trial information: NCT01813370.