Docetaxel-thalidomide combo shows benefit in prostate cancer

San Antonio-Researchers continue to probe the effects of docetaxel (Taxotere) on prostate cancer in efforts to devise the most efficacious application of the compound. Combining the agent with thalidomide (Thalomid) appears to enhance survival in androgen-independent disease, according to a phase II National Cancer Institute study whose initial data appeared earlier this year.

The data suggested a trend toward improved survival in patients on the combination therapy, but did not achieve statistical significance owing to a brief median follow-up of 26.4 months. However, more current data from the same trial presented here at the AUA annual meeting confirm that trend. At a median follow-up of 46.7 months, the median survival of patients receiving docetaxel plus thalidomide was 25.9 months, compared with 14.7 months in those receiving docetaxel alone, a difference that achieved statistical significance.

The study also found that neither docetaxel alone nor the combination of docetaxel and thalidomide appears to be significantly affected by a common mutation within cytochrome P450, a collection of enzymes in the liver that has stymied other therapies in the past.

Avi S. Retter, MD, clinical associate in the branch of genitourinary malignancies at the National Cancer Institute, Bethesda, MD, explained the rationale behind the NCI's decision to explore the agent in combination with thalidomide.

"The study is a randomized phase II study of docetaxel and thalidomide versus docetaxel alone in androgen-independent prostate cancer. We saw some time ago that thalidomide had modest activity against prostate cancer, and we hypothesized that combining the anti-angiogenic effects of thalidomide with docetaxel might give us more bang for the buck," Dr. Retter told Urology Times.

The NCI team also stratified the effects of the therapy in patients with a mutation in the CYP2C19 enzyme, a component of the cytochrome P450 complex.

"P450 is a system where a lot of drugs are metabolized. 2C19 is an enzyme within P450 that acts on thalidomide to transform it into its active metabolite. A number of people have a variant of 2C19 that differs from the wild-type 2C19 found in the general population. We thought that the people with the variant 2C19 might be less likely to respond to thalidomide. That is why we undertook this extended study," Dr. Retter said.

The study compared two regimens:

The initial results of this trial, published last year (J Clin Oncol 2004; 22:2532-9), showed a trend toward survival. However, the follow-up was too short to determine significance. Now, at a median follow-up of 46.7 months, the benefits of the combination therapy have achieved statistical significance. The median survival of patients receiving the docetaxel-thalidomide combination is 25.9 months, compared with 14.7 months in those receiving docetaxel alone.

"We are continuing to follow these patients. As we get further out, we will likely update the survival data and will possibly stratify it again according to 2C19 status," said Dr. Retter.

"The take-home message right now is that this study was not powered to detect survival benefits as a primary endpoint. With that disclaimer in mind, the combination of docetaxel and thalidomide has shown a significant survival difference in patients with androgen-independent prostate cancer. Additionally, there is no statistically significant difference in survival when the data is stratified by 2C19 status. However, this is a small group of patients and further investigation of the effectiveness of thalidomide in patients with the 2C19 variant is warranted," he said.

Targeted therapy

The rationale behind these and similar studies is to combine agents that target the biologic mechanisms of cancer cells on differing fronts. Docetaxel interrupts mitosis. Thalidomide inhibits the ability of tumors to recruit the new blood vessels necessary to sustain growth.