Annals of Oncology Advance Access published online on July 16, 2009
Annals of Oncology, doi:10.1093/annonc/mdp270
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Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC)
1 Drug Development Unit, Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK
2 Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa
3 Department of Medicine, University of Florida, Gainesville
4 Department of Medicine, Seattle Cancer Care Alliance, Seattle
5 Department of Medicine, University of Chicago, Chicago
6 Gloucester Pharmaceuticals, Inc., Cambridge, USA
* Correspondence to: Dr J. de Bono, Section of Medicine, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research and Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8722-4029; Fax: +44-20-8642-7979; E-mail: johann.de-bono{at}icr.ac.uk
Background: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC).
Patients and methods: A dose of 13 mg/m2 was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (Ho = 0.10, Ha = 0.30; 
and β = 0.10).
Results: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting 
6 months, along with a confirmed prostate-specific antigen decline of 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity.
Conclusions: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.
histone deacetylase, phase II, prostate cancer, romidepsin
Received for publication January 5, 2009. Revision received March 31, 2009. Accepted for publication April 1, 2009.