Paris--Adding a form of high-dose calcitriol to docetaxel (Taxotere) offers improved survival over docetaxel alone in men with metastatic androgen-independent prostate cancer, according to results of a multicenter trial presented at the 13th European Cancer Conference (ECCO-13) here. Further, the addition of the calcitriol formulation, known as DN-101, to the chemotherapy agent produced an unanticipated advantage in a reduced number of serious gastrointestinal and thromboembolic adverse events.
Paris-Adding a form of high-dose calcitriol to docetaxel (Taxotere) offers improved survival over docetaxel alone in men with metastatic androgen-independent prostate cancer, according to results of a multicenter trial presented at the 13th European Cancer Conference (ECCO-13) here. Further, the addition of the calcitriol formulation, known as DN-101, to the chemotherapy agent produced an unanticipated advantage in a reduced number of serious gastrointestinal and thromboembolic adverse events.
"DN-101 has a unique safety profile, and it appears to improve the toxicity of docetaxel. We need confirmatory evidence," said Tomasz Beer, MD, director of the Prostate Cancer Program, Oregon Health & Science University Cancer Institute, Portland, and lead investigator of the double-blind, randomized Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT).
A confirmatory trial is planned for this year to compare DN-101 plus docetaxel versus docetaxel plus prednisone. ASCENT-2, the phase III trial, will have survival as the primary endpoint. Enrollment is scheduled to begin in first-quarter 2006.
Epidemiologic data link vitamin D deficiency to a variety of tumor types, including prostate cancer. Preliminary studies found that high-dose calcitriol, a naturally occurring hormone and vitamin D receptor ligand, showed promising activity in prostate cancer by enhancing the action of chemotherapeutic agents in producing anti-tumor activity. A similar effect has not been seen with low-dose calcitriol.
ASCENT randomized 250 patients with previously untreated metastatic androgen-independent prostate cancer to weekly treatments with docetaxel, 36 mg/m2 , given intravenously for 3 weeks of a 4-week cycle. They received either DN-101, 45 µg, or placebo 1 day prior to their docetaxel treatment, and all received ongoing androgen deprivation therapy.
At median follow-up of 18.3 months, 229 patients (92%) were off treatment. One-half of all patients (49%) died. No significant difference between treatment arms was observed for PSA response at 6 months: PSA response was 49% in the docetaxel/placebo arm versus 58% in the docetaxel/DN-101 arm.
Median survival was 16.4 months in the placebo arm and has not been reached, but is estimated at 24.5 months in the DN-101 arm. Multivariate analysis showed that duration of survival was improved in patients who received DN-101 (HR, .67; p=.035). Median survival has been reached in the placebo arm, but it has not yet been attained in the DN-101 arm.
Other endpoints favoring DN-101 included the number of patients who had a 50% reduction in PSA at 6 months, time to PSA response, skeletal morbidity-free survival, and tumor response rates.
Exploratory analysis revealed an unanticipated favorable effect of DN-101 on serious adverse events, Dr. Beer said. Serious adverse events at a median of 18.3 months were reported in 41% of the placebo group and 27% of the DN-101 group (p=.023); grade 3 or 4 adverse events occurred in 70% and 58% of patients, respectively.
Dr. Beer said a possible explanation for this effect was that vitamin D receptor ligands decrease tissue factor expression and increase expression of thrombomodulin a protein that activates protein C, an endogenous anticoagulant. In addition, the ligands have been shown to reduce proliferation of epithelial cells in the gastrointestinal tract.