Antisense Oligonucleotide Custirsen Combined With Docetaxel and Prednisone in Metastatic Prostate Cancer
In the phase III SYNERGY trial reported in The Lancet Oncology, Chi et al found that the addition of the second-generation antisense oligonucleotide custirsen to docetaxel and prednisone did not improve overall survival in patients with metastatic castration-resistant prostate cancer. Custirsen inhibits the production of clusterin, a chaperone protein that is upregulated by apoptotic stressors and associated with treatment resistance.
Study Details
In the open label-trial, 1,022 patients with no prior chemotherapy from 134 sites in 12 countries were randomized between December 2010 and November 2012 to receive custirsen, docetaxel, and prednisone (n = 510) or docetaxel and prednisone (n = 512). All patients received intravenous docetaxel at 75 mg/m² on day 1 and prednisone at 5 mg twice daily in 3-week cycles; custirsen was given as three loading doses of 640 mg before day 0 followed by 640 mg intravenously on days 1, 8, and 15 of each cycle. The primary endpoint was overall survival in the intent-to-treat population.
Overall Survival
Median follow-up for surviving patients was 21.7 months in the custirsen group and 20.4 months in the control group. Median overall survival was 23.4 months (95% confidence interval [CI] = 20.9–24.8 months) in the custirsen group vs 22.0 months (95% CI = 19.5–24.0 months) in the control group (hazard ratio [HR] = 0.93, P = .415). There was no difference between the groups in the secondary endpoint of proportion of patients alive without a progression event on day 140 (57% vs 58%, odds ratio = 0.96, P = .800). Anticancer therapy after disease progression was given to 75% and 76% of patients.
Adverse Events
The most common grade ≥ 3 adverse events in the custirsen group were neutropenia (grade 3 = 13% vs 6% in control group; grade 4 = 20% vs 15%), febrile neutropenia (grade 3 = 10% vs 6%; grade 4 = 1% vs < 1%), and fatigue (grade 3 = 11% vs 8%; grade 4 = 1% vs < 1%). Serious adverse events occurred in 43% vs 36%. Treatment-related adverse events led to death in 5% of patients in both groups.
The investigators concluded: “Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone.”
The study was funded by OncoGenex Technologies.
Kim N. Chi, MD, of The University of British Columbia, BC Cancer Agency, is the corresponding author of The Lancet Oncology article.
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