Objective To determine the efficacy and toxicity of danusertib (formerly PHA-739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. Patients and Methods In this open-label, multicentre phase II trial 88 patients were randomly assigned (1: 1 ratio) to receive either danusertib 330 mg/m(2) over 6 h i.v. on days 1, 8 and 15 (arm A, n=43) or 500 mg/m(2) over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks. The primary endpoint chosen for this exploratory study was PSA response rate at 3 months. Results Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint. Median progression-free survival was 12 weeks in both arms. PSA response occurred in one patient in each arm; best overall response was stable disease in eight (18.6%) and 13 (34.2%) patients in arms A and B, respectively. Eleven out of 81 (13.6%) treated patients had stable disease for >= 6 months. Danusertib was generally well tolerated; the most common grade 3 and 4 drug-related adverse event was neutropenia which occurred in 37.2% (arm A) and 15.8% (arm B) of the patients. Conclusion Danusertib monotherapy shows minimal efficacy in patients with castration-resistant prostate cancer. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization.