Background: Custirsen (OGX-011) is a second generation antisense oligonucleotide (ASO) with a prolonged tissue half-life, greater potency and less toxicity than first-generation ASOs (CCR, 2008; 14(3): 833-839). Custirsen inhibits the expression of clusterin, a stress-induced, cytoprotective chaperone protein that is up-regulated in various cancers. In prostate cancer, clusterin expression is increased after androgen ablation or chemotherapy and contributes to treatment resistance. In vitro and in vivo studies show that the targeted knockdown of clusterin by custirsen results in increased sensitivity to cancer therapies (CCR, 2010; 16(4):1088-93). In a phase I neoadjuvant study, custirsen concentrations achieved in prostate tissue at the 640 mg dose level resulted in >94% decreases in clusterin expression and increased apoptosis (JNCI, 2005; 97(17): 1287-1296). Phase II studies have been completed in mCRPC, breast and lung cancer. In one phase II study, 82 patients with mCRPC randomized to receive docetaxel/prednisone (DOC/P) alone or DOC/P plus custirsen (640 mg IV weekly), median overall survival (OS) was 16.9 and 23.8 months in the two groups respectively, at a median follow-up of 35 months (JCO, 2010, 28:4247-4254). The phase III study, SYNERGY, will confirm whether adding custirsen to standard 1st line DOC/P treatment slows tumor progression and enhances survival beyond DOC/P alone. Methods: SYNERGY is a randomized, open-label, multi-center, international trial that is planned to enroll 800 patients with mCRPC. Chemotherapy-naïve patients will receive either DOC/P q 21d or DOC/P plus custirsen (640 mg IV weekly) until disease progression or unacceptable toxicity. The primary outcome measure is OS. Additional analyses include progression-free survival at Day 140 and Day 225, safety of custirsen combined with DOC/P, PSA measurements, and the association of efficacy measures with reduction of serum clusterin levels. All randomized patients will be included in the primary and secondary analyses (intent-to-treat analysis). The study was initiated in Sept, 2010 with an expected full accrual within 2 years. NCT01188187.