SAN FRANCISCOAtrasentan (ABT-627), an investigational
endothelin-A receptor antagonist made by Abbott Laboratories, appears to delay
clinical progression, PSA progression, and bone progression in
hormone-refractory prostate cancer patients, according to phase II clinical
trials presented at the 37th Annual Meeting of the American Society of Clinical
Michael A. Carducci, MD, assistant professor of oncology,
Johns Hopkins University School of Medicine, reported on 244 evaluable
asymptomatic patients of 288 patients who had been randomized in nine countries.
Two thirds of the patients were in Europe, and all had a life expectancy of less
than 12 months. Their median age was 70, and 200 patients experienced disease
He said that the median time to clinical progression
increased from 129 days in patients given placebo to 184 days in patients given
2.5 mg of atrasentan daily and to 196 days when the dose was increased to 10 mg
(P < .05) (Figure 1). The median time to PSA progression also lengthened from 71
days for the placebo arm to 155 days for patients who received 10 mg of
atrasentan (P < .05) (Figure 2). Patients treated with the 10-mg dose also gave better
quality-of-life reports than the placebo patients, Dr. Carducci said. Survival
data are not yet available.
The most common adverse events were peripheral edema (35% vs
14% of the placebo group), rhinitis (28% vs 13%), and headache (20% vs 10%).
Joel N. Nelson, MD, co-director of the Prostate and
Urological Cancer Center, University of Pittsburgh Medical Center, analyzed
pooled data from 419 patients with hormone-refractory prostate cancer from Dr.
Carducci’s study and from a second trial of atrasentan in symptomatic patients.
He looked at several biomarkers of bone progressionserum markers of bone
formation (total and bone alkaline phosphatase) (see Figure 3) and markers of
bone resorption such as collagen cross-linked urine N-telopeptides and urine
At baseline, the serum markers and markers of bone resorption
were elevated 2.2- to 3.6-fold above normal levels. Dr. Nelson reported that in
patients receiving the 10-mg dose of atrasentan, biomarker levels did not
increase further. The biomarkers continued to escalate in patients who received
2.5 mg of atrasentan, but not as much as in the placebo group.
The researchers then looked at bone scans following treatment
in a subset of patients. "There was significantly more bone progression for
the patients on placebo, compared to those on the drug," Dr. Nelson
commented. "This was the first demonstration of any drug having this
Viewed together, Drs. Carducci and Nelson’s reports suggest
that endothelin-A receptors are a new target for chemotherapy against
osteoblastic disease, said Donald Trump, MD, deputy director for clinical
investigations, University of Pittsburgh Cancer Institute.
"The trial results clearly suggest that bone progression
is inhibited and strongly mandate confirmatory trials, as are planned," Dr.
Trump said, alluding to two phase III trials that are scheduled to open this
Both investigators forecast the organization of additional trials. Dr.
Carducci spoke of testing atrasentan in combination with cytotoxic therapies and
in other cancers with bone progression. "It’s a completely new area for
intervention in advanced prostate cancer," said Dr. Nelson, suggesting that
trials with early-stage prostate cancer are also likely.