Atrasentan Prolongs Time to Progression in Prostate Cancer Patients

July 1, 2001

Phase II data presented at the 37th annual meeting of the American Society of Clinical Oncology showed that atrasentan

Phase II data presented at the 37th annual meeting ofthe American Society of Clinical Oncology showed that atrasentan (ABT-627), Abbott Laboratories’ investigationalendothelin-A receptor antagonist, delayed disease progression in patients withend-stage or hormone-refractory prostate cancer, allowing them to remain in afavorable state of health similar to baseline for a longer period of time,compared to placebo. Results from this study demonstrated that patients treatedwith 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-blindstudy were randomized to receive an oral dose of atrasentan at 2.5 or 10 mg oncedaily or placebo. The quality of life of study participants was measured usingthe 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 toprogression for patients treated with10 mg of atrasentan was significantly longer than the placebo group in mostdomains of the EORTC and FACT instruments (P < .05). Overall, patientstreated 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 toprogression over placebo. Improvement in the latter end point also correlatedwith 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 ofatrasentan vs placebo were peripheral edema (35% vs 14%), rhinitis (29% vs 13%),and headache (20% vs 10%). These adverse events were mild to moderate andassociated with few discontinuations of therapy.

Progression of Bone Metastases inEnd-Stage Prostate Cancer

Atrasentan can also inhibit the progression of bone metastasesin patients with end-stage or hormone-refractory prostate cancer, according tothe results of two other multinational, double-blind, phase II trials. Datapooled from a total of 419 men with hormone-refractory prostate cancer showedthat taking a 10-mg oral dose of atrasentan once daily maintained levels of keybiochemical markers, including serum total and bone alkaline phosphatase,consistent with the levels measured at the start of the study. This result wassignificantly different from the re-sult in patients taking placebo, whoexperienced increases in the levels of these biochemical markers (P < .001).

"These data suggest that atrasentan may have an impact onthe progression of hormone-refractory prostate cancer by delaying thedevelopment of skeletal metastases," said Joel Nelson, MD, professor andchairman of urology, University of Pittsburgh Medical Center and leadinvestigator in the study. "Skeletal metastases are indicative oflate-stage prostate cancer. This study is promising for late-stage prostatecancer."

Bone Markers

Bone markers of metastatic disease progression were measured atthe start of the study and compared to measurements taken subsequently. Inpatients receiving atrasentan, a dose-dependent response was observed; inpatients receiving the 10-mg dose of atrasentan, the total and bone alkalinephosphatase concentrations remained consistent with baseline levels. This resultwas statistically significant, compared to the results in patients takingplacebo, in whom increases in all markers ranged from 20% to 97% (P < .005). Patients receiving the 2.5-mg dose of atrasentanexperienced increases in biochemical markers that were lower than the increasesseen in patients taking placebo.

The most common adverse events with the 10-mg dose of atrasentanvs placebo were peripheral edema (39% vs 19%), rhinitis (28% vs 12%), headache(23% vs 12%), and constipation (22% vs 12%). These adverse events again weremild to moderate and associated with few discontinuations of therapy.

"We are excited to be presenting results from these phaseII studies that suggest that atrasentan may impact hormone-refractory prostatecancer," said Azmi Nabulsi, MD, head of clinical development for atrasentanat Abbott. "Elevated levels of biochemical markers indicate the spread ofcancer to the bone. This study indicates that blocking the effects of theendothelin-1 protein may play a role in delaying the progression of prostatecancer."

Phase III clinical investigations of atrasentan in patients withhormone-refractory prostate cancer are currently underway.