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