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Custirsen, an Antisense Oligonucleotide, May Enhance Docetaxel Efficacy in Hormone-Refractory Prostate Cancer

Custirsen, an Antisense Oligonucleotide, May Enhance Docetaxel Efficacy in Hormone-Refractory Prostate Cancer

ABSTRACT: Custirsen is designed to inhibit clusterin, a protein associated with reduced apoptosis and chemotherapy resistance in prostate cancer.

CHICAGO—The combination of custir-sen sodium (OGX-011, OncoGenex Technologies Inc), an investigational agent, with docetaxel (Taxotere) or mitoxantrone has acceptable toxicity in patients with hormone-refractory prostate cancer who have experienced a failure of first-line docetaxel-based chemotherapy, investigators reported at ASCO 2008 (abstract 5002). Efficacy outcomes were somewhat better with the custirsen/docetaxel combination.

Dr. Fred Saad

The protein clusterin inhibits treatment-induced apoptosis and has been associated with treatment resistance in prostate cancer, said lead investigator Fred Saad, MD.

“Custirsen is a second-generation antisense oligonucleotide designed to reduce clusterin production,” he explained. “It facilitates tumor cell death by lowering apoptotic threshold and sensitizing cancer cells to a variety of anticancer therapies.”

Participants in the open-label, randomized, noncomparative phase II trial were men with metastatic, hormone-refractory prostate cancer who had received at least two cycles of a docetaxel-based first-line regimen and had progressed while on this treatment or within 6 months afterward. They were given loading doses of custirsen followed by weekly custirsen plus docetaxel every 3 weeks and daily prednisone (CDP), or by weekly custirsen plus mitoxantrone every 3 weeks and daily prednisone (CMP).

Median follow-up of the trial population was 17.2 months, said Dr. Saad, a urologic surgeon at the University of Montreal. Results were based on 20 patients in the CDP arm and 22 in the CMP arm. Some 50% in the former arm and 36% in the latter arm received all nine planned cycles of therapy.

PSA Levels Fall

In the CDP group, all but one patient had a reduction from baseline in PSA levels, with values falling by 5% to 100%. In the CMP arm, half of patients had a reduction, with values falling by 5% to 80% (see Figure). Analyses of the entire trial population showed that median survival was significantly longer for patients whose PSA levels fell by more than 30% (19.4 vs 9.7 months).

Median progression-free survival was 7.2 months with CDP and 4.2 months with CMP, and corresponding median overall survival was 14.7 and 11.4 months.

In the entire population, overall survival was significantly longer in patients whose mean postbaseline clusterin level was 55 µg/mL or lower (14.7 vs 6.1 months, P = .002), suggesting that levels of the protein predict survival in this context, Dr. Saad observed.



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