Novel prostate cancer therapies focus on multiple targets

San Francisco-The next 2 years could be pivotal for novel agents and novel therapeutic strategies to treat advanced prostate cancer.

"There is no shortage of targets in prostate cancer and no shortage of trials," said Michael Carducci, MD, professor of oncology and urology at the Johns Hopkins Kimmel Cancer Center, Baltimore, at the 2008 Genitourinary Cancers Symposium held here.

Major completed phase III trials for hormone-resistant prostate cancer include CALGB 90401 (the tubulin-binding agent docetaxel [Taxotere] with or without the monoclonal antibody bevacizumab [Avastin]); VITAL-1 (GVAX immunotherapy versus docetaxel); and a study of the vaccine sipuleucel-T (Provenge). ASCENT II, which examined docetaxel with or without DN101, a formulation of calcitriol, was closed in November 2007 because of efficacy concerns with the experimental arm.

Positive results from GVAX and/or sipuleucel-T studies would suggest that immune therapy be administered before other therapies based on docetaxel. If both GVAX and sipuleucel-T study findings are positive, clinicians would have limited indications in which immune therapy should be used first.

The closure of ASCENT II suggested that more attention to safety profiles is needed in phase III trials, according to Dr. Carducci. The more advanced the disease, the more difficult it may be to find a positive effect and appropriate safety profile from the study. Phase III trials still under way include SWOG 0421 (docetaxel with or without atrasentan [Xinlay]), VITAL-2 (docetaxel with or without GVAX), and a study of docetaxel with or without vascular endothelial growth factor A-Trap.

Dr. Carducci said that every advance in prostate cancer biology provides new potential targets, which encourage another round of therapeutic development.

A number of chemotherapeutic agents are being studied following taxane treatment failure. Promising candidates include abiraterone and XRP6258.

Immune modulation is another approach under intense scrutiny. Potential agents include tumor antigen vaccines, autologous dendritic cells, and small molecule modulators. Small molecule immune modulating agents "are not ready for prime time," Dr. Carducci said, but are showing promise in phase II studies.

Exploratory results from dose-ranging studies of GVAX immunotherapy show a survival advantage for higher doses, Dr. Carducci reported. Median survival for high-dose regimen patients was 29.1 months, compared to 20 months on a mid-dose regimen and 23.1 months on a low-dose regimen.

Study results of sipuleucel-T, a dendritic cell-based agent, showed as a secondary exploratory endpoint a median survival benefit of 4.5 months compared to placebo: 25.9 months for the treatment group and 21.4 months for the placebo group. There was a non-significant benefit in time to progression: 11.7 weeks for the treatment arm against 10 weeks for the placebo arm. The agent's manufacturer recently launched the second of two phase II trials. A phase III study completed enrollment in October 2007.

"Immunotherapy for prostate cancer could soon be a treatment option," Dr. Carducci said.

The next steps include combination studies of immune modulation with other therapies. Current trials include combinations of GVAX with docetaxel (VITAL-2), cyclophosphamide (Cytoxan, Neosar), and androgen ablation.

Therapies targeting bone include bisphosphonates; radiopharmaceuticals plus docetaxel; denosumab, a receptor activator of nuclear factor-kappa B ligand inhibitor that targets osteoclasts; endothelin receptor antagonists atrasentan and ZD4054, both associated with osteoblast activity; and cathepsin K inhibitors, which target osteoclasts.

"We can expect important new information over the next year, but there is still a lot of room to explore targeted agents," Dr. Carducci said.