Background: A phase 2 study of the androgen receptor inhibitor ENZ as monotherapy in patients with HNPC [NCT01302041] showed a high prostate-specific antigen (PSA) response rate, regardless of baseline metastases, and favorable tolerability. In a 1- and 2-year follow-up, ENZ maintained long-term reductions from baseline in PSA, with minimal impact on total-body bone mineral density (BMD). Herein, results from a pre-specified 3-year follow-up are reported. Methods: A total of67 patients with HNPC and non-castrate testosterone ( ≥ 230 ng/dL) received ENZ 160 mg/day until disease progression or unacceptable toxicity. The primary end point of PSA response ( ≥ 80% decline from baseline) was analyzed at week 25 and 1, 2, and 3 years. Other end points were best overall tumor response, BMD, body composition, quality of life, and safety. Results: At the 3-year visit, 42 (62.7%) patients remained on the study medication. Of those, 38 (90.5%; 95% confidence interval 77.4%, 97.3%) maintained a PSA response. Of the 26 patients with metastases at baseline, 17 (65.4%) had a complete or partial response as best overall response at 3 years. In patients who completed the 3-year visit, minimal changes from baseline were observed in total-body BMD or in BMD of the femoral neck, trochanter, spine L1–L4, or forearm (median and mean changes ranged from –3.6% to 1.3% and –2.7% to –0.1%, respectively). The EORTC QLQ-C30 global health status results showed a small decrease at 3 years versus baseline (–3.96 points), consistent with the 2-year results. At 3 years, measurements for total body fat increased (median, 14.7%; mean, 16.5%) and total body lean decreased (median, –6.3%; mean, –6.5%) from baseline. Physical functioning, fatigue, and dyspnea worsened ( > 10 points) at 3 years, similar to results at 2 years. The most frequently reported adverse events ( > 10%) were gynecomastia, fatigue, hot flush, nipple pain, hypertension, diarrhea, nausea, pain in extremity, back pain, and constipation. Conclusions: In patients with HNPC treated with ENZ for 3 years, the efficacy of ENZ as monotherapy was maintained. Overall, BMD, global health status, and safety results were similar to those at 2 years. Clinical trial information: NCT01302041