Vitamin D, Taxotere Combination Promising For Advanced Prostate Cancer

Aug 8, 2005 /OHSU/ Results of a new study "strongly suggest" that in combination with docetaxel (Taxotere), DN-101, a new high-dose calcitriol pill designed specifically as a cancer therapy, extends the lives of men with advanced prostate cancer. The toxicity of the combination therapy proved to be no greater than for patients who received docetaxel alone. Calcitriol is a naturally occurring hormone and the biologically active form of vitamin D.

Tomasz Beer M.D.

"The data strongly suggest that DN-101, given in combination with docetaxel, will provide a substantial survival benefit to prostate cancer patients without adding toxicity," said Tomasz Beer, M.D., national leader of the clinical trial and director of the Prostate Cancer Program in the Oregon Health and Science University Cancer Institute. "While we've known about the anti-tumor potential of vitamin D, toxicity has been a significant issue to be overcome in making it a successful part of prostate cancer therapy."

Results from the study, the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT), were presented on Sunday, May 15, at the 41st annual meeting of the American Society for Clinical Oncologists in Orlando, Fla. Christopher Ryan, M.D, member of the OHSU Cancer Institute, served as principal investigator at the OHSU study site. The study was supported by Novacea Inc., maker of DN-101, in collaboration with Sanofi-Aventis, maker of Taxotere.

ASCENT is a randomized, double-blinded, placebo-controlled clinical trial to evaluate DN-101 in combination with docetaxel for advanced prostate cancer research subjects who are no longer responding to hormonal therapy, a condition known as androgen-independent prostate cancer (AIPC). Two hundred fifty subjects participated in the study at 48 sites between September 2002 and January 2004.

Researchers estimate that subjects receiving DN-101 in combination with docetaxel survive 7.1 months longer than those who received docetaxel alone. The U.S. Food and Drug Administration approved docetaxel as the standard of care for AIPC last year.

Survival benefits of the drug combination were confirmed by a prospectively planned multivariate analysis. The analysis showed ASCENT's survival data to be statistically significant (p=0.035) with a hazard ratio of 0.67. This means that subjects receiving DN-101 in combination with docetaxel appear to have a 49 percent increase in survival versus subjects taking docetaxel alone.

"The overall goal of the study was to confirm results from a small phase II OHSU study and to determine if this combination should be developed as a new treatment for advanced prostate cancer," Beer said. "Our results demonstrate that DN-101 has the potential to improve outcomes for patients and that moving forward with development of the drug is the right thing to do."

Overall survival was the secondary endpoint of ASCENT. The study's primary endpoint was a 50 percent or more reduction of prostate specific antigen (PSA), a protein made only by prostate cells. Certain prostate conditions, including prostate cancer, are associated with high levels of PSA in the blood.

Overall PSA responses occurred more frequently in subjects receiving the DN-101 plus docetaxel combination (63 percent) versus docetaxel alone (52 percent). While the difference between the two arms did not reach statistical significance (p=0.07), the combination results represent an historically strong PSA response. Six months into the study, 58 percent of DN-101 and 49 percent of placebo-treated patients had experienced a PSA response.

"During the past year, new work done by colleagues in the field has shown that only about half of survival can be explained by changes in PSA," Beer said. "Though PSA remains important, it has turned out to be a middle-of-the-road predictor of survival."

DN-101 works by producing much higher blood levels of calcitriol (1,25 dihydroxycholecalciferol) than the body can produce from dietary vitamin D or vitamin D supplements. In high doses, 1,25 dihydroxycholecalciferol enhances many commonly used chemotherapeutic agents, producing anti-tumor activity in laboratory and animal models.

Beer and W. David Henner, M.D., are the inventors of DN-101. Henner is a former OHSU faculty member. Henner has joined Novacea Inc., the company formed to develop DN-101, to play a key role in the development of the drug. Beer has been testing effects of high dose vitamin D on prostate cancer since the late 1990s.

Beer and OHSU have a significant financial interest in Novacea Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee, and the Integrity Program Oversight Council was implemented.

LINKS & Sources
ASCO presentation May 2005

An audio and slide show of Dr. Beer's presentation of the study findings is online at ASCO Virtual Meeting, here.

The written abstract of the study and links to the pill manufacturer are below. Also notice from 2003 of the patent for DN-101.

Interim results from ASCENT: A double-blinded randomized study of DN-101 (high-dose calcitriol) plus docetaxel vs. placebo plus docetaxel in androgen-independent prostate cancer (AIPC). Abstract no. 4516.

T. M. Beer, C. W. Ryan, P. M. Venner, D. P. Petrylak, G. Chatta, J. D. Ruether, W. D. Henner, K. N. Chi, S. Cruickshank, ASCENT Investigators

Background: High doses of calcitriol enhance the antitumor activity of multiple classes of chemotherapy in preclinical models and showed encouraging Phase 2 results in combination with docetaxel for AIPC. DN-101 is a new high-dose oral formulation designed to conveniently and reliably deliver the high calcitriol concentrations required for cancer therapy. Methods: Patients (pts) had metastatic AIPC, testosterone < 50 ng/ml, adequate organ function, clinical or PSA progression after anti-androgen withdrawal. Pts received weekly docetaxel 36 mg/m 2 iv for 3 weeks of a 4-week cycle with standard dexamethasone and either 45 µg DN-101 or placebo orally 1 day prior to docetaxel. The study was powered at 85% to detect a 20% improvement in the fraction of patients with a = 50% decline in serum PSA confirmed at least 4 weeks later (PSA response rate). Results: An interim analysis with a data cut-off of 6 months (June 2004) and median follow-up of 8 months is presented. 250 pts were randomized 1:1 at 48 sites in the US and Canada. Baseline characteristics were similar for both arms. PSA responses within 6 months (the primary endpoint) occurred more frequently in pts receiving DN-101 (58%) than placebo (49%), however this trend did not reach statistical significance (Cochran-Mantel-Haenszel chi square p=0.16). 102 patients had measurable disease. Objective response rate was 28% (3 CR, 10 PR of 46) vs. 20% (1 CR, 10 PR of 56) for DN-101 vs. placebo-treated patients. Most common grade 3/4 toxicities in the DN-101 and placebo-treated arms were neutropenia (8% vs. 8%), fatigue (7% vs. 15%), and hyperglycemia (6% vs. 11%). Serious adverse events occurred less frequently in DN-101 treated pts (24% vs. 36%, p=0.038). A similar trend was observed for AEs resulting in discontinuation of docetaxel (14% vs. 22% p=0.07). Conclusions: Early results show trends that favor DN-101 with respect to PSA and measurable tumor response rate and toxicity but do not reach statistical significance. Recommendations regarding further studies of DN-101 and docetaxel in AIPC will be made when the secondary endpoints of overall and progression-free survival are mature.