High-Dose Calcitriol Plus Docetaxel Compared With Placebo Plus Docetaxel In Androgen-Independent Prostate Cancer

Main Category: Urology / Nephrology
Also Included In: Prostate / Prostate Cancer;  Cancer / Oncology
Article Date: 05 Mar 2007 - 0:00 PDT

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UroToday.com- Calcitriol is the natural ligand for the Vitamin D receptor and is known to inhibit prostate cancer (CaP) proliferation, invasiveness, and angiogenesis and to induce apoptosis. DN-101 is a high concentration formulation of calcitriol produced by Novacea, Inc for use in cancer therapy. Calcitriol in combination with docetaxel was shown in a phase II trial to result in a 50% or greater decline in PSA in 81% of patients with androgen-independent prostate cancer (AICAP). Based upon this observation, the multicenter ASCENT trial was performed comparing docetaxel in combination with either DN-101 or placebo in 250 patients with AICAP. The results authored by Tomasz Beer, MD et al., appear in the February 20, 2007 issue of the Journal of Clinical Oncology.

The primary endpoint of the ASCENT trial was to evaluate the proportion of patients achieving a PSA response (>50% PSA reduction). Secondary objectives included overall survival and tumor and clinical progression-free survival. A sample size of 116 patients per treatment arm was calculated to provide 85% power to detect a 20% absolute increase in the PSA response rate.

DN-101 (45ug) or placebo was given orally on day 1 followed by docetaxel 36mg/m2 intravenously on day 2 along with dexamethasone weekly for 3 consecutive weeks. Treatment continued until disease progression, unacceptable toxicity or patient request for discontinuation. Patients on androgen-deprivation therapy were maintained on it during the trial. Patients meeting criteria for PSA response had the option to continue their treatment in the form of intermittent chemotherapy. Patient assessment was performed every 4 weeks.

At the time of data analysis the median duration of follow-up was 18.3 months, 229 patients have completed study treatment and 122 patients (49%) have died. A greater than 50% PSA decline was reached in 49% of placebo-treated patients and 58% of DN-101 treated patients (P=0.16). At any time while on this study, the PSA endpoint was reached in 52% of placebo patients and 63% of DN-101 treated patients (P=.07). Median time to PSA response was 5.3 months in the placebo group and 2.9 months in DN-101 treated patients (P=.06). Median duration of PSA progression-free survival was 7.6 months in placebo patients and 7.9 months in the DN-101 group. Tumor response by RECIST criteria was not significantly different. The median duration of skeletal morbidity-free survival trended in favor of DN-101 (13.4 months) over placebo (11.9 months). While the median survival in the placebo group was 16.4 months, it has not been reached in the DN-101 group, but is estimated to be 24.5 months using the adjusted Hazard Ratio. Overall, no increased toxicity was noted by the addition of DN-101 to docetaxel.

This study provides compelling data for the addition of DN-101 to docetaxel in the treatment of AICAP. A phase III trial (ASCENT-2) will compare weekly DN-101 plus weekly docetaxel to the standard 3-weekly docetaxel therapy.

Tomasz M. Beer, Christopher W. Ryan, Peter M. Venner, Daniel P. Petrylak, Gurkamal S. Chatta, J. Dean Ruether, Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M. Waterhouse, Michael A. Carducci, Daniel Vicario, Robert Dreicer, Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi, W. David Henner, Alan Arroyo, and Fong W. Clow
J Clin Oncol 2007;25:669-674.

Reviewed by UroToday.com Contributing Editor Christopher P. Evans, MD

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