Background: Although abiraterone acetate (AA), a CYP17 inhibitor, increases survival in men with metastatic castration resistant prostate cancer (mCRPC), tumors eventually progress on therapy. The primary purpose of this study was to identify mechanisms of resistance to AA via analysis of the androgen receptor signaling pathway in serial tumor biopsies of men receiving AA and dutasteride (DUT), a type I and II 5-α reductase inhibitor. In this analysis, we report secondary endpoints including prostate specific antigen (PSA) response, toxicity, and incidence of flare. Methods: We enrolled 40 men with mCRPC. Patients initially received AA (1,000 mg daily) and prednisone (5 mg daily). After two months (mos), DUT (3.5 mg daily) was added. Therapy was continued until radiographic progression. A flare was recorded on bone scan, CT, or both if there were worsening lesions from baseline to 3 mos, decreasing PSA more than 50% from baseline at 3 mos, and stabilization or reduction of lesions at 6 mos. Results: Median follow-up was 13 mos. At the time of analysis, nine men remain on treatment. Twenty five percent and 18% of men received prior therapy with ketoconazole and/or chemotherapy, respectively. The median PSA at baseline was 28.8 ng/mL. After 2 mos of AA, median PSA declined by 54% to 10.9 ng/mL. Median PSA nadir was 6.3 ng/mL, reached at a median of 3.2 mos from baseline. 34 men (85%) experienced some degree of PSA decline. Twenty four men (60%) had a greater than or equal to 50% PSA decline and 12 (30%) had a greater than or equal to 90% PSA decline, reached at a median of 1.4 and 2.4 mos from baseline, respectively. There were 73% grade 1, 23% grade 2, 4% grade 3, and no grade 4 adverse events (AEs).AEs of interest included fatigue (45%), hypertension (38%, n=2 grade 3), hypokalemia (15%, n=0 grade 3), liver function test increases (15%), and edema (2%, n=0 grade 3). Seventeen men had imaging available for analysis, of whom four (23%) had flare on both 3 mos CT and bone scan and four (23%) had flare on only 3 mos CT scan. Conclusions: Given time of median PSA nadir, DUT may enhance efficacy of AA, though this warrants further investigation. Therapy with AA, prednisone (5 mg daily), and DUT is well tolerated with low rates of severe mineralocorticoid toxicity. Flare is seen on imaging in 47% of patients receiving AA. Biopsy data evaluating mechanisms for resistance to AA are not yet available. Clinical trial information: NCT01393730.