Atrasentan reduces cancer risk by 20 percent in men with advanced hormone-resistant prostate cancer

Recent clinical studies led by Johns Hopkins Kimmel Cancer Center researchers have found that a drug called atrasentan reduces the risk by 20 percent that cancer will progress in men with advanced hormone-resistant prostate cancer. The results are expected to be presented at the 40th Annual American Society of Clinical Oncology (ASCO) meeting on June 5 in New Orleans.

"Treatment options remain limited for patients whose prostate cancer has spread and does not respond to hormone therapy, and some of these men are looking for less toxic alternatives than chemotherapy at this point in their lives," says Michael Carducci, M.D., associate professor at the Johns Hopkins Kimmel Cancer Center. "Atrasentan can help prevent their pain and may potentially postpone when they need more aggressive treatments like chemotherapy or radiation."

Combined results of phase II and phase III international clinical trials, which spanned three years and enrolled more than one thousand men, showed an approximately 20 percent decrease in the chance that their cancer will progress in those who took atrasentan daily versus a placebo.

"This drug's largest effect may be its ability to stabilize the progression of prostate cancer to the bone," says Carducci. "As a result, atrasentan slows the rise in PSA levels and delays the development of pain while maintaining quality of life." Few patients experienced side effects such as a stuffy nose, headache, and swelling.

Part of a new trend in cancer treatment, known as "targeted therapy," atrasentan blocks a protein called endothelin, which is secreted in excess amounts by prostate cancer cells. Endothelin promotes cancer cell growth and stimulates new bone formation where prostate cancer cells have spread to bone sites. Recent studies elsewhere confirm that endothelin is a key protein involved in the type of bone metastasis that commonly occurs in prostate cancer.

The phase II trial enrolling 244 patients with metastatic hormone refractory prostate cancer was completed in 2001, and showed atrasentan delayed disease progression by 52 percent as compared to men receiving a placebo. Analysis of the phase III data alone did not show a difference in disease progression between the 804 patients randomized to receive atrasentan or the placebo. But when combined with the results of the Phase II study, investigators observed a statistically significant difference between the drug and its control in the length of time it took for the disease to progress. Both randomized, double-blind studies were similar in design and enrolled patients with hormone resistant prostate cancer that had metastasized or spread.

Carducci plans to continue studies of atrasentan in patients whose cancer has not spread and in combination with other drugs that block growth factors. He adds that atrasentan could potentially be an option after second-line hormonal therapy or when patients are waiting to begin chemotherapy. Hopkins and other centers nationwide will study the drug in patients with brain, renal cell, ovarian and lung cancers.

The identification of endothelin and its role in prostate cancer as a potential target for therapy led to the development of atrasentan and was first described nine years ago in Hopkins laboratories through a specialized program of research excellence (SPORE) grant from the National Cancer Institute.

Co-authors are Joel B. Nelson from the University of Pittsburgh, F. Saad from University of Montreal, Canada; C.C. Schulman from Erasme Hospital, Brussels, Belgium; D.P. Dearnaley from Royal Marsden Hospital, London; D.J. Sleep, S.M. Hulting, J.D. Isaacson, A.R. Allen, and P. Nisen from Abbott Laboratories.