PURPOSE In patients who received enzalutamide, we characterized the development of radiographic progression (rPD) without prostate-specific antigen (PSA) rise or progression in metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC). Methods We conducted a post hoc analysis in two phase III trials (N = 2,551; ARCHES [ClinicalTrials.gov identifier: NCT02677896 ]; PROSPER [ClinicalTrials.gov identifier: NCT02003924 ]) for co-occurrence of rPD ± Prostate Cancer Working Group 2/3-defined PSA progression, and rPD ± any PSA rise from baseline/nadir by treatment. Kaplan-Meier methods were used for overall survival (OS) outcomes. RESULTS In ARCHES, 3.5% and 8.5% of 574 patients with mHSPC treated with enzalutamide plus androgen-deprivation therapy (ADT) had no PSA rise or PSA progression at rPD, respectively. Of 79 patients with rPD who received enzalutamide plus ADT, 25.3% had no PSA rise and 62.0% did not meet PSA progression criteria compared with 7.4% and 38.3% of 188 patients with rPD treated with ADT alone, respectively. In PROSPER, 4.4% and 10.3% of 933 patients with nmCRPC treated with enzalutamide plus ADT had no PSA rise or PSA progression, respectively, at rPD. However, of 187 patients with rPD who received enzalutamide plus ADT, 21.9% had no PSA rise and 51.3% did not meet PSA progression criteria compared with 3.6% and 18.8% of 224 patients treated with placebo/ADT, respectively. Liver metastases were >5-fold higher in enzalutamide-treated patients with rPD events versus control, although sample size was small. Compared with no rPD, enzalutamide-treated patients with rPD ± PSA rise or progression had worse OS. CONCLUSION Given the frequent discordance and poor prognosis of imaging-based progression in the absence of PSA changes during enzalutamide treatment in mHSPC and nmCRPC, periodic surveillance using imaging is recommended.