Background: We have previously shown in an animal model of IAAT that blocking testosterone (T) to DHT by a 5α-reductase inhibitor (5ARI) has a more significant effect on tumor growth in a "regressed" prostate, ie previously treated with AAT, than in an "intact" prostate. It was also observed that 5ARI significantly inhibited tumor proliferation, but only early in the regrowth phase. A randomized phase II trial was done in which dut or placebo was given during the regrowth phase and a prostate biopsy was done to measure tumor proliferation. Methods: Eligible patients (pts) had metastatic, castrate-sensitive prostate cancer and had an intact prostate (no previous surgery or XRT). Treatment consisted of AAT for 8 months. Responding pts were randomized to receive dut (0.5 mg daily) or placebo during the regrowth phase. When serum T normalized, pts underwent a research biopsy of the prostate and then were resumed on AAT. Responding pts were then crossed-over to receive dut or placebo during the second regrowth phase. When T normalized, a second research biopsy was done and the pts resumed AAT. PSA levels were measured monthly to determine PSA doubling time (PSADT). Tumor proliferation was measured by Ki-67 index. Statistical analysis was by students t-test. Results: 21 pts were enrolled onto the study. 16 pts were randomized to dut vs placebo and 11 pts underwent prostate biopsies. Dut resulted in significant inhibition of tumor proliferation as measured by Ki-67 index compared to placebo (3.65 ± 1.7 vs 8.5 ± 2.3, p=0.001). PSADT during the regrowth phase was similar between the 2 groups. Dut was well tolerated without significant toxicities. Conclusions: The clincial observation of an early inhibitory effect of 5ARI on tumor proliferation during regrowth of a regressed (treated) prostate is novel and was similar to that observed in our animal xenograft model of IAAT. This suggests that using a 5ARI during the regrowth phase of IAAT and using T normalization as the trigger for resumption of AAT may result in improved efficacy of this treatment. This study was supported in part by NIH Grant P50 CA90386 (Prostate SPORE). Clinical trial information: NCT00668642.