Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study

inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers. METHODS: Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1). RESULTS: A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies. CONCLUSION: Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience

Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure

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

Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure.

Abstract Study Type - Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Since their discovery aurora kinases have been identified as a potential target in anticancer therapy and currently many aurora-selective small molecule kinase inhibitors are in development. Aurora kinases play an essential role as key mitotic regulators and are frequently overexpressed in prostate cancer. In vivo data in the transgenic mouse prostate carcinoma model revealed tumour regressions of >80% in three out of 16 animals and disease stabilizations in 10 out of 16 animals treated with danusertib. Two phase I dose escalation studies with danusertib in patients with advanced solid tumours were performed, which established two doses and schedules for phase II studies. However, the preliminary data of the available phase II studies with danusertib in solid tumours showed limited activity. Danusertib may yield more activity in the treatment of leukaemias than in solid tumours. Danusertib is generally well tolerated with neutropenia as the main dose limiting toxicity. This phase II study determined the efficacy and toxicity of danusertib administered intravenously over two different dosing schedules in patients with metastatic castration-resistant prostate cancer (CRPC) with progressive disease after docetaxel-based treatment. Danusertib showed in vivo antitumour activity in prostate cancer models and clinically relevant disease stabilizations were observed in several patients with solid tumours in phase I studies. However, our study revealed that monotherapy with danusertib, although well tolerated, showed only limited activity in the treatment of patients with CRPC. In view of the new advances in the treatment of patients with CRPC and the negative result of our study it is unlikely that danusertib will be further explored for the treatment of patients with CRPC. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization to select subsets of patients with CRPC who may benefit from treatment with danusertib. 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