SYNERGY: Adding Custirsen to Docetaxel plus Prednisone Regimen Does Not Improve Outcomes in Patients with Metastatic Prostate Cancer
Custirsen is a second-generation antisense oligonucleotide that inhibits production of human clusterin, a prosurvival chaperone protein upregulated in tumor cells in response to apoptotic stressors such as chemotherapy. Chi and colleagues reported the results from the SYNERGY study, a randomized multicenter, international, phase 3 clinical trial, which assessed whether in patients with metastatic castrate-resistant prostate cancer (mCRPC), the addition of custirsen to standard first-line chemotherapy with docetaxel plus prednisone would prolong overall survival (OS) versus docetaxel plus prednisone alone (Chi K, et al. ESMO 2014: Abstract 755O).
A total of 1022 patients with chemotherapy-naïve mCRPC were randomized in a 1:1 ratio to receive the combination of docetaxel plus prednisone alone or the combination plus intravenous custirsen 640 mg weekly, for up to 10 cycles or until disease progression, unacceptable toxicity, or withdrawal. The final analysis showed that after a target of 509 events, the median OS was 23.4 months with the addition of custirsen to the docetaxel plus prednisone combination versus 22.2 months with the combination alone, an insignificant difference (P = .21).
Subsequent therapy with abiraterone, enzalutamide, or cabazitaxel was used in 75% and 76% of patients receiving either the 3 drugs or the 2-drug combination, respectively. More patients in the docetaxel plus prednisone plus custirsen arm than in the docetaxel plus prednisone arm discontinued treatment because of treatment-related adverse event (41% vs 29%, respectively); the most common grade 3 or 4 adverse events were fatigue, febrile neutropenia, asthenia, diarrhea, pulmonary embolism, and pneumonia, with hematologic toxicities consisting of neutropenia, lymphopenia, and anemia.
Therefore, the addition of clusterin to first-line chemotherapy with docetaxel plus prednisone did not significantly improve OS in patients with mCRPC and was furthermore associated with increased toxicity.