OHSU Cancer Institute Researcher Find Drug Combination Helps Halt Prostate Cancer

02/04/08  Portland, Ore

A high-dose activated vitamin D pill combined with docetaxel, a chemotherapy drug, extends the lives of men with advanced prostate cancer.

A high-dose activated vitamin D pill combined with docetaxel, a chemotherapy drug, extends the lives of men with advanced prostate cancer. And, there was no increase in toxic side effects with the combination of drugs as compared with taking docetaxel alone, according to a study published in the Feb. 20 issue of the Journal of Clinical Oncology by Oregon Health & Science University Cancer Institute principal investigator Tomasz M. Beer, M.D., national leader of the clinical trial.

The high-dose pill, DN-101, was designed specifically for cancer therapy. Calcitriol is a natural occurring hormone and the biologically active form of vitamin D. DN-101 delivers activated vitamin D in amounts that are far higher than the natural levels of this hormone.

Results from the study are part of the Androgen Independent Prostate Cancer (AIPC)  Study of Calcitriol Enhancing Taxotere (ASCENT). The study was sponsored by Novacea Inc., maker of DN-101, and supported by 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. Two hundred fifty subjects participated in the study at 48 sites in the United States and Canada***

Survival benefits of the drug combination were confirmed by a multivariate analysis that showed that patients who received the combination of DN-101 and docetaxel had a 49 percent increase in survival versus subjects taking docetaxel alone (p=0.035).

"The principal 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 resoundingly that DN-101 has the potential to substantially improve outcomes for patients." Beer is the director of Prostate Cancer Research at the OHSU Cancer Institute, associate professor of medicine, (hematology/medical oncology) OHSU School of Medicine.

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 blood levels of PSA.

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.

An unexpected outcome of the ASCENT trial was that cancer patients taking calcitriol also experienced a reduction in blood clots an Oregon Health & Science University Cancer Institute team has found. These results of the clinical trial were recently published in the British Journal of Haematology. Thrombosis, or blood clots, is a serious complication in advanced cancers and affects between 15 percent and 20 percent of all cancer patients.

Novacea Inc, the maker of DN-101, is pursuing further development of the DN-101 plus docetaxel combination in a phase III randomized study with the primary endpoint of overall survival.

DN-101 is produced by Novacea Inc. OHSU and Beer have significant financial interest in Novacea  Inc., a company that has 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.