BACKGROUND: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. OBJECTIVE: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo). INTERVENTION: Patients received 240mg/d apalutamide while continuing on androgen-deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). RESULTS AND LIMITATIONS: A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. CONCLUSIONS: In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. PATIENT SUMMARY: Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01171898.