Phase II data presented at the 37th annual meeting of the American Society of Clinical Oncology showed that atrasentan (ABT-627), Abbott Laboratories’ investigational endothelin-A receptor antagonist, delayed disease progression in patients with end-stage or hormone-refractory prostate cancer, allowing them to remain in a favorable state of health similar to baseline for a longer period of time, compared to placebo. Results from this study demonstrated that patients treated with an oral 10-mg dose of atrasentan once daily experienced nearly a 30% improvement in quality-adjusted time to disease progression.
Significantly Longer Time to Progression
The 288 patients in this phase II multinational, double-blind study were randomized to receive an oral dose of atrasentan at 2.5 or 10 mg once daily or placebo. The quality of life of study participants was measured using the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ) C-30 and Functional Assessment of Cancer Therapy-Palliative (FACT-P) instruments.
A Kaplan-Meier analysis showed that the quality-adjusted time to progression for patients treated with 10 mg of atrasentan was significantly longer than the placebo group in most domains of the EORTC and FACT instruments (P < .05). Overall, patients treated with the 10-mg or 2.5-mg dose of atrasentan experienced an average 28% or 38% increase, respectively, in the median quality-adjusted time to progression over placebo. Improvement in the latter end point also correlated with a statistically significant delay in clinical and prostate-specific antigen (PSA) progression for patients taking atrasentan.
The most common adverse events associated with the 10-mg dose of atrasentan vs placebo were peripheral edema (35% vs 14%), rhinitis (29% vs 13%), and headache (20% vs 10%). These adverse events were mild to moderate and associated with few discontinuations of therapy.
Progression of Bone Metastases in End-Stage Prostate Cancer
Atrasentan can also inhibit the progression of bone metastases in patients with end-stage or hormone-refractory prostate cancer, according to the results of two other multinational, double-blind, phase II trials. Data pooled from a total of 419 men with hormone-refractory prostate cancer showed that taking a 10-mg oral dose of atrasentan once daily maintained levels of key biochemical markers, including serum total and bone alkaline phosphatase, consistent with the levels measured at the start of the study. This result was significantly different from the re-sult in patients taking placebo, who experienced increases in the levels of these biochemical markers (P < .001).
"These data suggest that atrasentan may have an impact on the progression of hormone-refractory prostate cancer by delaying the development of skeletal metastases," said Joel Nelson, MD, professor and chairman of urology, University of Pittsburgh Medical Center and lead investigator in the study. "Skeletal metastases are indicative of late-stage prostate cancer. This study is promising for late-stage prostate cancer."
Bone markers of metastatic disease progression were measured at the start of the study and compared to measurements taken subsequently. In patients receiving atrasentan, a dose-dependent response was observed; in patients receiving the 10-mg dose of atrasentan, the total and bone alkaline phosphatase concentrations remained consistent with baseline levels. This result was statistically significant, compared to the results in patients taking placebo, in whom increases in all markers ranged from 20% to 97% (P < .005). Patients receiving the 2.5-mg dose of atrasentan experienced increases in biochemical markers that were lower than the increases seen in patients taking placebo.
The most common adverse events with the 10-mg dose of atrasentan vs placebo were peripheral edema (39% vs 19%), rhinitis (28% vs 12%), headache (23% vs 12%), and constipation (22% vs 12%). These adverse events again were mild to moderate and associated with few discontinuations of therapy.
"We are excited to be presenting results from these phase II studies that suggest that atrasentan may impact hormone-refractory prostate cancer," said Azmi Nabulsi, MD, head of clinical development for atrasentan at Abbott. "Elevated levels of biochemical markers indicate the spread of cancer to the bone. This study indicates that blocking the effects of the endothelin-1 protein may play a role in delaying the progression of prostate cancer."
Phase III clinical investigations of atrasentan in patients with hormone-refractory prostate cancer are currently underway.