Although better data won’t be available until Phase 3 tests have been completed, the results of Phase 1 and 2 trials suggest that this drug will slow — possibly stabilize or reduce — pca progression for at least half a year for 2/3 of users. Side effects are minor, with no dose-limiting toxicity yet seen. It appears that this drug could be used with existing therapies. Given this situation I would recommend trying for the Phase 3 trials, which are currently in progress at various locations. This drug is a delaying action, not a cure. It blocks a messenger protein that instigates cell proliferation and other bad things. It does not kill cells.

Atrasentan (generic name) is an oral drug that — used as a monotherapy -- delays the progression of advanced pca [1]. It does so by blocking the cancer cell receptor for autocrine endothelin protein, an instigator of cell proliferation. It is a small molecule that inserts itself preferentially into receptor A intended for endothelin-1.

This same endothelin-1 process occurs in colorectal, ovarian, breast, cervical, glioma, and pancreatic cancers.

Atrasentan also affects (I am not sure which way) the rate of bone breakdown (osteoclastic resorption).

The short effective period (5 months) for this therapy seems to indicate that the cancerous cells are able, by mutation, to eventually circumvent this drug.

A Phase 1 dose escalation study was reported in 1999. A group of 26 hrpc patients were given 2.5-95 mg atrasentan [2]. No dose-limiting toxicity was seen. After 1 mo. of treatment, 19 of 26 patients had an initial decline in PSA or a stabilization of the disease as determined by CT scan and bone scintigraphy. Two patients had stable disease for more than 11 and 15 months. This trial indicates a response in the area of two-thirds, but a duration of response that may extend to a year or more.

In a second Phase 1 trial [3], doses of 10-75 mg/day were given for 28 days. Toxicity was similarly benign. Ten of the 15 patients experienced declines in PSA of 5-48%. Thus, 2/3 of the men experienced stabilization or reduction in their PSA values.

A two-part multinational Phase 2 clinical study [4,5,6,7] was reported in 2001. Different numbers (288 and 244) of patients were used to establish different findings (10 mg, 2.5 mg and placebo arms).

A Phase 1 dose escalation study was reported in 1999. A group of 26 hrpc patients were given 2.5-95 mg atrasentan [2]. No dose-limiting toxicity was seen. After 1 mo. of treatment, 19 of 26 patients had an initial decline in PSA or a stabilization of the disease as determined by CT scan and bone scintigraphy. Two patients had stable disease for more than 11 and 15 months. This trial indicates a response in the area of two-thirds, but a duration of response that may extend to a year or more.

In a second Phase 1 trial [3], doses of 10-75 mg/day were given for 28 days. Toxicity was similarly benign. Ten of the 15 patients experienced declines in PSA of 5-48%. Thus, 2/3 of the men experienced stabilization or reduction in their PSA values.

A two-part multinational Phase 2 clinical study [4,5,6,7] was reported in 2001. Different numbers (288 and 244) of patients were used to establish different findings (10 mg, 2.5 mg and placebo arms).

Of 244 patients who received 10 mg atrasentan, time to disease progression was 196 days vs. 129 days for placebo. (Results for the 2.5 mg dose were slightly less than the 10 mg dose.) Progression was defined as a worsening of the disease to a point that required intervention, to the onset of pain, or to the appearance of new bone lesions. Although these are subjective assessments, they were done under double-blind conditions. No response rate was given.

An assessment of QOL showed a 30% improvement for the 10 mg Atrasentan, another highly subjective evaluation. No response rate was given.

In an assessment of bone markers, objective results were obtained for 419 men out of both trial sections. For patients receiving 10 mg atrasentan, the serum total and bone alkaline phosphatase markers remained stable. No response rate was given.

One section of the study used PSA and a quantitative indicator called the Bone Scan Index. (This Bone Scan Index is simply a mathematical tool for quantifying—comparatively—the extent of tumor invasion as determined from bone scans.) Atrasentan showed a slowing trend in the progression of bone lesions. All bone markers showed a delay in the time to progression. Median time to PSA progression (for the entire group that received 10 mg doses) was 20 weeks, while men on placebo progressed in 8 weeks.

The 20-week time period covers every individual who received the atrasentan, including—presumably—some who did not respond. Therefore, I would expect from the Phase 3 trials that this time period would increase when only that group of individuals who respond are included. The data available so far suggest that about 2/3 of the users respond, and the median duration of response is longer than 5 months.

Atrasentan is an antagonist for the endothelin A receptor. No other applications were reported for this drug.

The drug target is the receptor that allows endothelin communication back into the cell. The endothelins are a group of vasoconstrictors, three of which are chemically related to asp venom. Stress—an accepted carcinogen--is also an exogenous vasoconstrictor. Vasoconstrictor drugs are used to counter hypotension and to maintain blood pressure in case of hemorrhage.

The Phase 1 trials showed no dose-limiting toxicity up to a dose of 95 mg/day. Side effects in the Phase 2 trial (10 mg) were mild to moderate, with one person discontinuing: peripheral edema (35%), rhinitis (29%), and headache (20%)

What is the status in the drug development pipeline? When will it be available?

Phase III drug trials are in progress at various locations around the country. Availability is TBD. See the following web page -

http://abbott.com/innovation/clinical_trials_atrasentan.cfm. 

Also read the AUA 2002 abstract listed below(8).

Oral, 10 mg, once-a-day. The Phase 1 trials suggested that a higher dose might offer slightly higher effectiveness. With no toxicity reported up to 95 mg/day, it should not be a problem, for example, to double the dosage.

Synergistic effects? Conflicting drugs? Because the toxicity is low, this drug could be probably be used with other, more toxic therapies. No drug interactions were reported.

Where do you obtain it? Cost?

It is not available at present. The only source is Abbott Laboratories, and they would be dispensing it for the Phase 3 trial.

1. Abbott Laboratories web site, http://www.abbott.com/news/.

2. BA Zonnenberg et al., "Results of an initial Phase I dose-escalation study of the Endothelin-A Receptor Antagonist ABT-627 in Patients with Hormone Refractory Prostate Cancer," ASCO 1999.

3. M. Carducci et al., "ABT-627, an Endothelin-Receptor antagonist for Refractory Adenocarcinomas: Phase I and Pharmacologic Evaluation," ASCO 1999.

4. M. Carducci et al., "The Endothelin-A Receptor Antagonist Atrasentan (ABT-627) Delays Clinical Progression in Hormone Refractory Prostate Cancer: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial," ASCO 2001, No. 694.

5. JB Nelson et al., "The Endothelin-A Receptor Antagonist Atrasentan (ABT-627) Reduces Skeletal Remodeling Activity in Men with Advanced, Hormone Refractory Prostate Cancer," ASCO 2001, No. 12.

6. T Guise et al., "Endothelin A Receptor Blockade Inhibits Osteoblastic Metastases," ASCO 2001, No. 331.

7. A Singh et al., "The Selective Endothelin-A Receptor Antagonist Atrasentan Improves Quality of Life Adjusted Time to Progression (QATTP) in Hormone Refractory Prostate Cancer Patients," ASCO 2001, No. 1567.

8. AUA 2002 Abstract #705, Claude Schulman*, Bruxelles, Belgium; Joel B Nelson, Pittsburgh, PA; Mark A Weinberg, Rod A Humerickhouse, Jennifer L Schmitt, Azmi A Nabulsi, And The Atrasentan Clinical Research Group, Abbott Park, IL, "ATRASENTAN DELAYED PSA PROGRESSION IN A PHASE II TRIAL OF MEN WITH HORMONE REFRACTORY PROSTATE CANCER."

Evaluation by: Bob Benson and Howard Hansen

Revised: 7/22/02. Most recent update  10/31/07 (HH).