Studies show promise for new, existing prostate cancer drugs

New York-Several promising agents in early stages of development may find a role in the treatment of prostate cancer, and two ongoing cooperative group trials will provide more definitive evidence about how best to use docetaxel (Taxotere) in the treatment of hormone-refractory prostate cancer (HRPC). At the Mount Sinai School of Medicine Chemotherapy Foundation Symposium here, the developments were reviewed by Noah M. Hahn, MD, assistant professor of medicine at the Indiana University Cancer Center in Indianapolis.

"Phase III ongoing studies in the cooperative group setting will have the biggest impact on our practices," Dr. Hahn said.

Histone deacetylase (HDAC) inhibitors are involved in the silencing and upregulation of many genes implicated in cancer, Dr. Hahn explained. Suberoylanilide hyroxamic acid (SAHA), a small-molecule inhibitor of histone deacetylase, is the most potent HDAC inhibitor in clinical development. SAHA targets most human class I and class II enzymes, with no effect on class III enzymes. This agent can be administered orally and has excellent bioavailability, Dr. Hahn said.

Clusterin inhibitors have shown encouraging results thus far. Clusterin is a chaperone protein that facilitates proteosome degradation and is upregulated in hormone-refractory disease. In preclinical models, an antisense oligonucleotide against clusterin has been shown to prolong time to disease progression and enhance taxane activity. Preclinical proof of principle has been shown in prostate, lung, and other solid tumors. OGX-011 is being studied in multiple trials in breast, prostate, and lung cancer. A phase II trial comparing docetaxel versus OGX-011 as front-line treatment of prostate cancer is ongoing.

Microtubule inhibitors have been used in the treatment of prostate cancer for many years. A new microtubule inhibitor, which is a halichondrin B analog, has shown preclinical activity in prostate cancer and in taxane-resistant ovarian cancer cell lines, according to Dr. Hahn. An Eastern Cooperative Oncology Group phase II study is being considered in prior taxane-treated or chemotherapy-naive prostate cancer patients. The study will include correlative markers to try to identify patients who will derive the most benefit from this drug.

Another development is a new formulation of albumin-bound paclitaxel (Abraxane) that makes it easier to use the drug. Preclinical models have shown increased efficacy compared with standard paclitaxel dosing regimens. Studies suggest that albumin-bound paclitaxel has improved activity over docetaxel in prostate cancer. Phase II trials are studying the new formulation as front-line therapy for hormone-refractory disease.

"Look for results of these studies," Dr. Hahn said.

Pemetrexed (Alimta) is a multitargeted anti-folate agent originally developed for non-small cell lung cancer that targets many enzymes involved in cancer. An ongoing phase II study of pemetrexed as second-line therapy for hormone-refractory prostate cancer has just finished accrual. A preliminary analysis of patients in this study showed some PSA responses, but further data are needed to determine the effectiveness of this drug in prostate cancer, Dr. Hahn said.

In the cooperative group setting, the Cancer and Leukemia Group B (CALGB) and the Southwest Oncology Group (SWOG) are accruing patients with hormone-refractory disease for randomized controlled trials.

CALGB 90401 will enroll more than 1,000 patients and will randomize them to receive docetaxel plus prednisone with or without bevacizumab (Avastin). SWOG 0421 will include more than 900 patients and will randomize them to receive docetaxel plus prednisone with or without atrasentan (Xinlay). Dr. Hahn urged the audience to enroll patients in these trials.

All of the drugs Dr. Hahn mentioned are promising, said session moderator Anna Ferrari, MD, associate professor of oncology and co-director of the genitourinary cancer program at New York University Cancer Center. She singled out halichondrin B, a microtubule inhibitor, and said preliminary data are encouraging and that this drug may turn out to be more effective than docetaxel.

"Clusterin is a fascinating molecule," she said. "We know this molecule protects cells from being degraded. My opinion, based on the heterogeneity of prostate cancer, is that OGX-011 will probably have limited utility as a single agent, but it may tip the balance toward improved efficacy when combined with other agents."