NEW YORK—A high-dose oral formulation of calcitriol, called DN 101 and used in combination with docetaxel, is associated with longer survival in men with hormone-refractory prostate cancer (HRPC), according to a recent study.


“DN 101 overcomes the limitations of prior calcitriol formulations,” explained Kim N. Chi, MD, assis-tant professor of medicine at the University of British Columbia in Vancouver. “Prior to DN 101, patients had to take large numbers of capsules to get enough calcitriol.” He presented findings here at the Chemotherapy Foundation Symposium sponsored by the Mount Sinai School of Medicine.

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The study, called ASCENT (Androgen-lndependent Prostate Cancer [AIPC] Study of Calcitriol Enhancing Taxotere), enrolled 250 men with metastatic, progressive HRPC. Men were randomized to receive docetaxel plus DN 101 or docetaxel plus placebo.


The DN 101 arm experienced fewer grade 3 and 4 adverse events than the placebo group (58% vs. 70%) and fewer serious adverse events (41% vs. 27%), especially GI and thromboembolic events. One third of men taking DN 101 had grade 1 hypercalcemia, but they required no treatment and no clinically relevant sequelae occurred.


The primary endpoint (PSA response at six months) was reached in 58% of patients in the DN 101 arm compared with 49% of the placebo recipients. Overall PSA response was seen in 63% and 52%, respectively. Time to PSA response was 2.9 months and 5.3 months, respectively. These differences between treatment arms were not statistically significant. Median survival in the DN 101 arm was 24.5 months compared with 16.4 months in the placebo arm. “This represents a one third reduction in risk of death,” Dr. Chi said.


Follow-up study planned


The findings are sufficiently promising to justify a large phase III, multicenter, international, randomized trial called ASCENT-2 to further evaluate the combination. The trial will enroll 900 patients with metastatic HRPC randomized to receive either DN 101 45 µg combined with docetaxel 36 mg/m2 weekly for three out of four weeks or standard docetaxel 75 mg/m2 once every three weeks. Unlike ASCENT, the primary end point will be overall survival, which is considered to be the most important outcome, Dr. Chi said. Secondary end points include skeletal-related events, risk of toxic adverse events, exploratory PSA response, and pain and quality of life.


The rationale for high-dose calcitriol stems from epidemiologic studies suggesting that vitamin D deficiency plays a role in prostate cancer. Supraphysiologic doses of calcitriol have been shown to have dose-dependent antitumor activity in preclinical models of prostate tumors. Previous studies with high-dose calcitriol demonstrated PSA declines of 50% or greater in 81% of patients with an overall one-year survival of 89%. This compares favorably with the literature on single-agent docetaxel, said Dr. Chi, adding that he was enthusiastic about the potential for DN 101 to improve outcomes.