The addition of custirsen to docetaxel and prednisone failed to improve overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase III open-label trial. Those with poor prognosis may derive benefit from the therapy, however.
Clusterin, a cytoprotective chaperone, is upregulated in response to chemotherapy and is associated with resistance to treatment. “Clusterin expression in prostate cancer is associated with relapse and progressive disease after successive treatments and with resistant disease with poor prognosis,” wrote study authors led by Kim N. Chi, MD, of the University of British Columbia in Vancouver. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production, enhancing some anticancer therapies.
After phase I and II studies showed promise combining custirsen with docetaxel and prednisone, researchers conducted the phase III SYNERGY trial in 1,022 men in 12 countries randomized to that combination or to docetaxel and prednisone alone. The results were published online ahead of print in Lancet Oncology.
The median overall survival with custirsen was 23.4 months, compared with 22 months without it, for a hazard ratio (HR) of 0.93 (95% CI, 0.79–1.10; P = .415). A secondary outcome measure, the proportion of patients alive and without a progression event on day 140, was also no different, at 57% with custirsen and 58% with docetaxel and prednisone alone, for an odds ratio of 0.96 (95% CI, 0.75–1.23; P = .800).
With custirsen, there was an increased incidence of pyrexia (35% vs 14%) and chills (34% vs 4%), which was primarily a result of infusion reactions. Other adverse events more common with the study drug included grade 3 or worse fatigue (11% vs 8%), febrile neutropenia (11% vs 7%), asthenia (7% vs 3%), and diarrhea (6% vs 3%). A total of 28 patients (6%) required custirsen dose reductions, while docetaxel reductions were required in 26% of custirsen patients and in 20% of docetaxel/prednisone patients.
A post-hoc subgroup analysis found that in patients with poor prognosis, those treated with custirsen had longer overall survival, at 17 months vs 14 months for an HR of 0.73 (95% CI, 0.59–0.90). Those with good prognosis saw no difference between the therapies.
The researchers wrote that the negative results of this trial were “unexpected,” given the positive phase II studies before it. Still, the benefit seen in poor prognosis patients is promising. “This work is hypothesis-generating and requires confirmation from further studies,” they wrote.