Randomized Phase II Study of Docetaxel and Prednisone With or Without OGX-011 in Patients With Metastatic Castration-Resistant Prostate Cancer Kim N. Chi, Sebastien J. Hotte, Evan Y. Yu, Dongsheng Tu, Bernhard J. Eigl, Ian Tannock, Fred Saad, Scott North, Jean Powers, Martin E. Gleave, and Elizabeth A. Eisenhauer From the British Columbia Cancer Agen- cy–Vancouver Centre; Vancouver Pros- tate Centre, Vancouver, British Columbia; Juravinski Cancer Centre, Hamilton; National Cancer Institute of Canada Clinical Trials Group, Kingston; Princess Margaret Hospital, Toronto, Ontario; Tom Baker Cancer Centre, Calgary; Cross Cancer Institute, Edmon- ton, Alberta; University of Montreal, Montreal, Quebec, Canada; and Univer- sity of Washington, Seattle, WA. Submitted November 2, 2009; accepted June 29, 2010; published online ahead of print at www.jco.org on August 23, 2010. Supported by Grant No. 013387 from the Canadian Cancer Society. Presented at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Kim N. Chi, MD, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, British Colum- bia, V5Z 4E6 Canada; e-mail: kchi@ bccancer.bc.ca. © 2010 by American Society of Clinical Oncology 0732-183X/10/2827-4247/$20.00 DOI: 10.1200/JCO.2009.26.8771 A B S T R A C T Purpose To determine the clinical activity of OGX-011, an antisense inhibitor of clusterin, in combination with docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 1:1 to receive docetaxel/prednisone either with (arm A) or without (arm B) OGX-011 640 mg intravenously weekly. The primary end point was the proportion of patients with a prostate-specific antigen (PSA) decline of  50% from baseline, with the experimental therapy being considered of interest if the proportion of patients with a PSA decline was more than 60%. Secondary end points were objective response rate, progression-free survival (PFS), overall survival (OS), and changes in serum clusterin. Results Eighty-two patients were accrued, 41 to each arm. OGX-011 adverse effects included rigors and fevers. After cycle 1, median serum clusterin decreased by 26% in arm A and increased by 0.9% in arm B (P  .001). PSA declined by  50% in 58% of patients in arm A and 54% in arm B. Partial response occurred in 19% and 25% of patients in arms A and B, respectively. Median PFS and OS times were 7.3 months (95% CI, 5.3 to 8.8 months) and 23.8 months (95% CI, 16.2 months to not reached), respectively, in arm A and 6.1 months (95% CI, 3.7 to 8.6 months) and 16.9 months (95% CI, 12.8 to 25.8 months), respectively, in arm B. Baseline factors associated with improved OS on exploratory multivariate analysis were an Eastern Cooperative Oncology Group perfor- mance status of 0 (hazard ratio [HR], 0.27; 95% CI, 0.14 to 0.51), presence of bone or lymph node metastases only (HR, 0.45; 95% CI, 0.25 to 0.79), and treatment assignment to OGX-011 (HR, 0.50; 95% CI, 0.29 to 0.87). Conclusion Treatment with OGX-011 and docetaxel was well tolerated with evidence of biologic effect and was associated with improved survival. Further evaluation is warranted. J Clin Oncol 28:4247-4254. © 2010 by American Society of Clinical Oncology INTRODUCTION Prostate cancer is the most common malignancy and a significant cause of morbidity and mortality in men. 1 Patients with advanced disease who ex- perience progression after medical or surgical cas- tration have limited therapeutic options, with docetaxel chemotherapy being the only approved systemic treatment demonstrating improved overall survival (OS). 2,3 In a phase III trial of docetaxel and prednisone given every 3 weeks, confirmed prostate-specific antigen (PSA) de- clines of  50% occurred in 45% of patients, and the median OS time was 19.2 months. 4 The clusterin (CLU) gene on chromosome 8p21-p12 has been linked to numerous physiologic and pathologic processes. 5 Clusterin functions as a cytoprotective chaperone similar to adenosine triphosphate–independent small heat shock pro- teins, 6 and its transcription is promoted by the an- drogen receptor 7 and by heat shock factor-1, a multifaceted mediator of carcinogenesis. 8 The amino acid sequence of clusterin is highly conserved across species; in humans, clusterin exists as cyto- plasmic and secretory forms, and a truncated nu- clear splice variant has also been described. 9 The cytoplasmic/secretory forms are associated with an- tiapoptotic functions through mechanisms that JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28  NUMBER 27  SEPTEMBER 20 2010 © 2010 by American Society of Clinical Oncology 4247 Downloaded from ascopubs.org by 54.90.169.225 on June 10, 2022 from 054.090.169.225 Copyright © 2022 American Society of Clinical Oncology. 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