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

• Published in: BJU international 2013-01, Vol.111 (1), p.44-52
• Main Authors: Meulenbeld, Hielke J., Bleuse, Jean P., Vinci, Elio M., Raymond, Eric, Vitali, Giordano, Santoro, Armando, Dogliotti, Luigi, Berardi, Rossana, Cappuzzo, Federico, Tagawa, Scott T., Sternberg, Cora N., Jannuzzo, Maria G., Mariani, Mariangela, Petroccione, Anna, Wit, Ronald
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; aurora kinase; aurora kinase inhibitor; Aurora Kinases; Benzamides - administration & dosage; Benzamides - adverse effects; Biological and medical sciences; Bone Neoplasms - secondary; Castration; castration‐resistant prostate cancer; Clinical trials; danusertib; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Gynecology. Andrology. Obstetrics; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Male genital diseases; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Neutropenia - chemically induced; PHA‐739358; Prostatic Neoplasms - drug therapy; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Taxoids - therapeutic use; Treatment Failure; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2012.11404.x

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 dan