Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 1-5, 2007.
Atrasentan is a potent, oral, selective endothelin-A (ETA) receptor antagonist that has clinical activity in patients with hormone-refractory prostate cancer (HRPC). In this article, the authors report the results from a phase 3, randomized, double-blind, placebo-controlled trial of atrasentan in patients with nonmetastatic HRPC.
Of 941 patients who had adequate androgen suppression and no radiographic evidence of metastases but rising prostate-specific antigen (PSA) levels, 467 patients were randomized to receive atrasentan at a dose of 10 mg, and 474 patients were randomized to receive placebo daily. The primary endpoint was the time to disease progression (TTP), which was defined as the onset of metastases. Secondary endpoints were the time to PSA progression, change in bone alkaline phosphatase (BALP) levels, PSA doubling time, and overall survival.
There was a 93-day delay in the median TTP with atrasentan, but the difference from placebo in TTP was not statistically significant (P = .288). Large geographic differences in the median TTP were noted: in the US: The difference was 81 days longer with placebo; whereas, in non-US sites, the difference was 180 days longer with atrasentan. Atrasentan lengthened the PSA doubling time (P = .031) and slowed the increase in BALP (P < .001). The median survival was 1477 days with atrasentan and 1403 days with placebo. The most common adverse events associated with atrasentan were peripheral edema, nasal congestion, and headache, consistent with the vasodilatory properties of ETA receptor antagonists.
Worldwide, more than 200,000 men die annually from metastatic hormone-refractory prostate cancer (HRPC), including more than 80,000 in Europe and an estimated 27,050 in the US.1, 2 Widespread use of medical castration has resulted in large numbers of men undergoing androgen-deprivation therapy (ADT) before they develop objective metastases. This practice has created a disease state defined by rising prostate-specific antigen (PSA) as the first and only sign of HRPC. In these otherwise asymptomatic men, delaying the emergence of objective metastatic disease is a worthwhile goal, particularly if the intervention also is well tolerated. Exploiting the generally slow progression of nonmetastatic HRPC, an effective therapy could convert this into a chronic illness in which overall mortality is no longer defined primarily by HRPC-specific death.
Since the profound response of prostate cancer to ADT first was described, 1 finding has remained unchanged: The initial effectiveness ultimately is lost. Eventually, approximately 85% of men with HRPC develop metastatic disease, predominantly in bone3; and, once these lesions develop, the prognosis is dire. Quality of life declines rapidly, primarily reflecting the morbidity associated with bone metastases,4 and the median survival for patients with progressive, castrate, metastatic HRPC who are treated with chemotherapy is only 16 to 18 months.5, 6
Endothelin-1 (ET-1) and the endothelin-A (ETA) receptor are implicated in prostate cancer progression.7–9 ET-1 is produced by normal prostatic epithelium and by primary and metastatic prostate cancer. Plasma ET-1 concentrations are higher in men with HRPC than in men with localized disease or in healthy volunteers. The predominant endothelin receptor on normal prostatic epithelium, ETB, commonly loses expression in prostate cancer, whereas the expression of ETA is increased and ultimately predominates as a consequence of transformation. Indeed, ETA receptor expression in prostate cancer cells increases with worsening histologic grade and disease stage.10, 11 ET-1 binding to the ETA receptor acts as a survival factor in a host of benign and malignant cells, including prostate cancer. For example, ET-1 reduces paclitaxel-induced apoptosis in prostate cancer in vitro, an effect that is prevented by ETA receptor blockade with the selective ETA receptor antagonist atrasentan; similarly, the combination of paclitaxel and atrasentan decreased prostate tumor growth in vivo significantly more than either agent alone.12
It is even more noteworthy that, in the setting of bone-metastatic HRPC, prostate cancer-derived ET-1 facilitates interactions between ET-1-secreting tumor cells and the bone microenvironment, where it acts as a mitogen for osteoblasts, which express ETA receptors at high density, and inhibits osteoclast bone resorptive activity and motility, resulting in new bone growth.13, 14 ET-1, acting through the ETA receptor, is causal in the development of osteoblastic metastases in animal models. Atrasentan, as a potent ETA selective receptor antagonist, significantly inhibits the development of osteoblastic response to cancer in bone in a variety of model systems.
Atrasentan has demonstrated clinical activity in patients with HRPC.15–17 In placebo-controlled, phase 2 and 3 clinical trials in patients with asymptomatic or symptomatic. metastatic HRPC, atrasentan delayed disease progression and PSA progression, improving progression-free survival (PFS) and attenuating the rise in bone alkaline phosphatase (BALP). Although treatment differences for some efficacy endpoints did not attain statistical significance for the intent-to-treat (ITT) population, they consistently were significant for the evaluable population in each trial. Coupling this clinical activity with preclinical evidence for the role of ET-1 and ETA in prostate cancer progression, the current trial was designed to test the hypothesis that atrasentan would delay the time to disease progression (TTP) in men with nonmetastatic HRPC.
MATERIALS AND METHODS
Eligible patients had histologically confirmed, nonmetastatic HRPC; had undergone surgical or pharmacologic castration (with maintenance androgen-suppression therapy) at least 3 months before randomization; and had castrate testosterone levels at screening. Before randomization, PSA levels were at least 20 ng/mL within 12 months, or had increased by 50% within 6 months (minimum, 1 ng/mL at screening), or were rising (2 sequential increases with a confirmatory third increase) within 12 months (minimum, 1 ng/mL at screening) with no radiographic evidence of metastases. Other inclusion criteria included a documented, minimum withdrawal period from antiandrogen therapy of 4 to 6 weeks before randomization; a Karnofsky performance score ≥70; no other malignancies except nonmelanoma skin cancer within the previous 5 years; and adequate hematologic, hepatic, and renal function.
Patients were ineligible if they were candidates for local salvage therapy or if they had received any of the following therapies for prostate cancer or associated pain: cytotoxic chemotherapy or radionuclides; external-beam radiotherapy, brachytherapy, or cryotherapy to the prostatic bed within 6 months before randomization; radiation therapy to a lesion outside the prostatic bed >6 months after either castration or initiation of hormone therapy; steroids within 6 months before randomization; or opioid analgesic therapy within 6 months before randomization. Prohibited treatments included hormonally active therapies (other than gonadotropin-releasing hormone agonists), intravenous or oral bisphosphonates, any investigational product within 4 weeks before randomization, or prior or current treatment with an endothelin antagonist. Patients with current cardiovascular disability (New York Heart Association Class 2 or greater); significant pulmonary disease requiring chronic or pulse steroid therapy within the preceding 3 months; or any clinically significant, unstable, uncontrolled disease were ineligible.
The institutional review boards or independent ethics committees of all participating investigational sites approved the protocol. Each patient or his legal representative signed and dated an approved informed consent form.
Eligible patients were assigned randomly in a 1:1 ratio to double-blinded, daily, oral administration of atrasentan at a dose of 10 mg or matching placebo on an outpatient basis. Study treatment continued until patients experienced confirmed disease progression or unacceptable adverse effects, decided to discontinue taking the study treatment or to discontinue participation in the study, or until the study was completed. Patients with confirmed disease progression and those who were active on study at the time the double-blind period ended (May 31, 2006) were eligible to enroll in an open-label extension study in which all participants received atrasentan at a dose of 10 mg daily. All patients were followed for survival at 3-month intervals after their final study visit until January 31, 2007.
If a patient experienced a treatment-related grade 3 or 4 toxicity according to National Cancer Institute Common Toxicity Criteria (version 2.0), the study drug was then interrupted until the toxicity resolved to within 1 grade level of baseline, but not exceeding grade 2. If the toxicity recurred, the study drug was then interrupted again, and it was reinstated upon resolution as described for the initial occurrence. A second recurrence required discontinuation of study drug. If resolution was not achieved within 2 weeks of study drug interruption, then the study drug was to be discontinued.
Evaluations to ensure that patients met eligibility criteria and to establish baseline values were performed during a 35-day screening period before randomization. The absence of bone and soft tissue metastases was evaluated by bone scans and chest/abdominal/pelvic computed tomography or magnetic resonance imaging scans, respectively, and was confirmed by centralized, independent review.
Eligible patients were enrolled and randomly assigned study drug on Day 1. Subsequent clinic visits, during which patients were assessed for safety and clinical evidence of disease progression, were conducted at Day 14; Weeks 4, 8, and 12; and every 6 weeks thereafter. Bone scans were obtained at Week 12 and thereafter at 12-week intervals and underwent centralized, independent review to determine whether there was disease progression. PSA and biochemical bone markers were evaluated at Weeks 4, 8, and 12 and every 12 weeks thereafter.
Any of the following events was indicative of disease progression: 1 or more new metastatic skeletal lesions observed on bone scan; 1 or more new metastatic extraskeletal lesions at least 1.5 cm in greatest dimension visible on computed tomography or magnetic resonance imaging scan; or an event attributed to metastatic prostate cancer (eg, upper urinary tract obstruction, spinal cord compression, pain) supported by radiographic, surgical, or pathologic evidence of disease. An increase in PSA was not considered disease progression. An independent radiologist(s) read all radiographs, and an independent oncologist(s) confirmed all disease progression events: Independent reviewers were blinded to randomization status. Safety was assessed by review of treatment-emergent adverse events, laboratory test results, and vital sign measurements.
TTP and PFS were the primary efficacy endpoints of the study for regulatory agencies in the US and Europe, respectively. TTP was defined as the time from randomization to onset of the earliest confirmed event of disease progression. PFS was defined as the time from randomization to the earliest onset of a confirmed event of disease progression, grade 3 or 4 hypercalcemia within 7 days of the last dose of study drug, or death within 42 days of the last available evaluation. All events of disease progression were confirmed by centralized, independent review. For TTP, data were censored at the date of the last available evaluation in the absence of a confirmed event of disease progression. For PFS, data were censored as described for TTP with the addition of a confirmed event of hypercalcemia or death.
Secondary efficacy endpoints were the time to onset of PSA progression (TTPSA), the mean change from baseline to final BALP value, PSA doubling time, and survival (measured without censoring data for subsequent treatments). TTPSA was defined as the time from randomization to the first of 2 or more consecutive postbaseline PSA measurements obtained ≥14 days apart that were at least 50% greater (minimum, 5 ng/mL increase) than the patient's PSA nadir. A patient's PSA nadir was defined as the smallest PSA value between his baseline and postbaseline PSA values measured through study drug dosing Day 105. Data for patients without PSA progression were censored at the date of the last postbaseline on-study or off-study PSA measurement obtained no more than 7 days after the last study drug dose. PSA doubling time was calculated by using the formula (natural logarithm of 2)/slope of the linear regression fit to natural logarithm of PSA versus time (years) relative to the first dose of study drug. PSA doubling times were categorized into the following intervals: >0 to 0.25 years, >0.25 to 0.5 years, >0.5 to 0.75 years, >0.75 to 1 year, >1 to 1.5 years, >1.5 to 2 years, and >2 years.
Tertiary efficacy endpoints included time to the first skeletal metastasis. All efficacy analyses were performed on all randomized patients.
The distributions of all time-to-event endpoints were estimated for each treatment group using Kaplan-Meier methodology, and comparisons between treatment groups were performed using a protocol-specified, weighted, log-rank G1,1 statistic18, 19 stratified by region (US sites vs non-US sites) and the Cox proportional hazards model. No stratification factors were used at randomization. For the primary and secondary time-to-event endpoints, the stratified G1,1 statistic was the primary statistic used for comparisons between treatment groups. The mean change from baseline to final value in biomarkers was calculated for each treatment group and was compared using an analysis of covariance with treatment group as the factor and baseline value as the covariate. The Cochran-Mantel-Haenszel mean score test was used to compare the rate of PSA rise, as determined by PSA doubling time categories, between treatment groups.
Safety was assessed for the following variables: study drug exposure; incidence of treatment-emergent adverse events, including deaths and other serious adverse events; laboratory data; and vital sign measurements. The Fisher exact test was used to compare the incidence of adverse events between treatment groups. Safety analyses included all patients who received at least 1 dose of study drug.
Data from an earlier study in patients with metastatic HRPC were the basis of simulations indicating the need to enroll 900 to 1000 patients to realize 650 events of disease progression and to attain 90% power to detect a 25% difference in TTP. Because the patient population in the current study had earlier stage disease, we determined that 500 events of disease progression would provide 80% power to detect a treatment difference using the log-rank test if the hazards ratio in favor of atrasentan was 0.77. We anticipated that 500 events of disease progression would be achieved by May 31, 2006, the primary cutoff date for statistical analyses. The cutoff date for data used in survival analyses was January 31, 2007.
Safety and efficacy data, summarized by treatment group, were reviewed by an independent data-monitoring committee during the course of the study. The committee met on 6 occasions to assess safety only and performed 2 formal interim analyses of safety and efficacy. Interim efficacy analyses were governed by a 1-sided, formal group sequential stopping rule,20 which was subject to constraints on the maximum allowed boundary.21 Statistical significance for all endpoints was determined by a 2-sided P value ≤.05.
Between July 2001 and April 2003, 941 patients were randomized at 75 investigational sites in the US and at 108 investigational sites outside of the US. Demographic and baseline characteristics generally were balanced between groups (Table 1). Figure 1 shows the allocation of patients to the placebo (N = 474) and atrasentan (N = 467) groups and patient disposition.
Table 1. Demographic and Baseline Characteristics
No. of Patients (%)
SD indicates standard deviation; PSA, prostate-specific antigen; BALP, bone alkaline phosphatase.
73.4 ± 7.79
73.9 ± 7.81
Karnofsky performance score
Enrollment by region
Time since initial diagnosis, y
Total no. of patients
Mean ± SD
7.2 ± 3.86
7.5 ± 4.03
Total no. of patients
Mean ± SD
29.8 ± 60.16
28.9 ± 54.64
Total no. of patients
Mean ± SD
14.3 ± 8.02
14.4 ± 7.73
Total Gleason score
Total no. of patients
TTP and PFS endpoints were included to satisfy regulatory authorities in the US and Europe, respectively. Because the results for both endpoints were similar, only those for TTP are presented here (Table 2). There was a 93-day delay in the median TTP with atrasentan (764 days) compared with placebo (671 days), but the difference in the distribution was not statistically significant (P = .288) (Fig. 2a). When the data were analyzed by region (US vs non-US), it became apparent that patients who were randomized to receive treatment with atrasentan at sites in the US had a shorter median TTP (590 days) than those at non-US sites (847 days), whereas the median TTP was similar for placebo patients across regions (US sites, 671 days; non-US sites, 667 days) (Table 2) (Fig. 2b).
Table 2. Analysis of Efficacy
TTP indicates time to progression; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; G1,1, a protocol-specified, weighted log-rank statistic; PSA, prostate-specific antigen; BALP, bone alkaline phosphatase; SE, standard error.
P value was determined using analysis of covariance with treatment group as the factor and with the baseline value as the covariate.
No. of patients
Median TTP, d
No. of patients
Median TTP, d
No. of patients
Median TTP, d
HR for TTP [95% CI]
Stratified G1,1P value
No. of patients
Median PFS, d
No. of patients
Median PFS, d
No. of patients
Median PFS, d
HR for PFS [95% CI]
Stratified G1,1P value
Overall survival: All sites
Median survival, d
HR for overall survival [95% CI]
Stratified G1,1P value
No. of patients
Median time to PSA progression, d
HR for PSA progression [95% CI]
Stratified G1,1P value
PSA doubling time, % of patients
No. of patients
PSA doubling time, y
P value using Cochran-Mantel- Haenszel mean score test
Overall, a significantly greater percentage of patients on atrasentan discontinued prematurely (33.2% vs 25.9%; P = .015). Premature discontinuations were significantly more frequent at US sites (40.8%) than at non-US sites (21.9%; P < .001). The cumulative discontinuation rates for patients on atrasentan versus patients on placebo at US sites were 45.5% and 36%, respectively; whereas, at non-US sites, the corresponding rates were 24.6% and 19.3%. Adverse events were the most frequent primary explanation by investigators for premature discontinuations, and the percentage of patients on atrasentan who discontinued for this reason was more than twice that of the patients on placebo overall (15.8% vs 7.4%, respectively) and by region (US sites: 20.9% vs 9.5%, respectively; non-US sites: 12.3% vs 6%, respectively). Although an increase in PSA was not considered disease progression according to the protocol, differences between US sites and non-US sites were noted in the mean PSA increase between the penultimate and last visits and the mean PSA values at the last visit for patients in both treatment groups (Table 3). In all patients, the mean increase in PSA and the mean PSA values were lower at US sites than at non-US sites. Similar proportions of patients discontinued treatment for protocol-defined PSA progression between the 2 arms (atrasentan vs placebo: 2.6% vs 3%), but the discontinuation rate for PSA progression at US sites was more than 4 times higher than that for non-US sites (20 of 380 patients [5.3%] vs 6 of 561 patients [1.1%]).
Table 3. Prostate-Specific Antigen Levels Among Patients Who Discontinued the Study
No. of Patients
Mean PSA, ng/mL
PSA indicates prostate-specific antigen.
A greater percentage of patients on placebo (56.3%) than patients on atrasentan (48.6%) had confirmed disease progression. New extraskeletal lesions and metastatic prostate cancer events were cited as the primary manifestation of disease progression by similar percentages of patients on placebo (8% and 4%, respectively) and patients on atrasentan (8.8% and 3.6%, respectively). However, new skeletal lesions were cited as the primary reason for disease progression by a greater percentage of patients on placebo (44.3%) than patients on atrasentan (36.2%). Treatment with atrasentan delayed the median time to initial presentation with skeletal metastases by approximately 250 days (1008 days for atrasentan vs 757 days for placebo), but the difference in the distribution was not statistically significant (P = .103).
The median TTPSA progression was similar for the 2 groups (254 days for the atrasentan group vs 253 days for the placebo group; P = .240). The rate of PSA rise, as measured by doubling time distribution, was significantly slower for atrasentan than for placebo (P = .031). Atrasentan significantly attenuated the rise in BALP from baseline to final assessment (mean change: −1.51 ng/mL on atrasentan vs +2.21 ng/mL on placebo; P = .001).
The median survival was 1477 days on atrasentan and 1403 days on placebo in the ITT population (hazards ratio, 0.919; 95% confidence interval, 0.769-1.098) (Fig. 3). It is difficult to interpret results regarding the possible effect of atrasentan on overall survival, because the survival data were not censored for subsequent treatment, and 54% of the patients on placebo subsequently enrolled in the open-label study and received atrasentan.
Common treatment-emergent adverse events that were reported significantly more often with atrasentan included peripheral edema, nasal congestion, headache, dyspnea, and anemia (P ≤ .029). With placebo, these included constipation and hypertension (P ≤ .006) (Table 4). Most of these events reported with atrasentan were grade 1 or 2 and resolved during the treatment period with or without the use of ancillary medication. Generally, the median time to onset of these events was within the initial 30 days; the median time to onset of anemia was 225 days after starting treatment. Most important, there was no evidence of cumulative toxicity. All these events had been observed in patients who received atrasentan in earlier clinical trials. Peripheral edema, nasal congestion, dyspnea, and headache are consistent with the vasodilatory effects of ETA receptor blockade, whereas anemia reflects an underlying mechanism of plasma volume expansion resulting in hemodilution. Initial decreases in hemoglobin at 2 weeks for atrasentan-treated patients were accompanied by increases in weight and decreases in white blood cell (WBC) and albumin concentrations, all suggestive of volume expansion. After 2 weeks, hemoglobin, WBC, and albumin levels stabilized, and the changes paralleled those observed with placebo, both for the duration of the study and after study drug discontinuation.
Treatment-emergent AEs were coded using the Medical Dictionary for Regulatory Activities, version 9.0.
P values for pairwise comparisons were determined using the Fisher exact test with a significance level of P < .05. If no P value is shown, then the difference was not statistically significant.
Anemia and hypertension are not included in the table, because the incidence was <15% in each group (anemia: 7.9% in the placebo group vs 12.3% in the atrasentan group; P = .029; hypertension: 10.4% in the placebo group vs 3.7% in the atrasentan group; P < .001).
The incidence of grade 3 or 4 hypertension was 1.9% in the placebo group and 0.6% in the atrasentan group.
A greater percentage of patients in the atrasentan group (26.4%) than in the placebo group (16.4%) experienced adverse events that resulted in discontinuation of study drug. Serious adverse events occurred with similar frequency in both treatment groups (Table 4). The incidence of deaths resulting from serious adverse events also was similar between the atrasentan group (3.5%) and the placebo group (4.7%).
ET receptor antagonists, as a group, have demonstrated an increased incidence of cardiopulmonary events that likely is related to their underlying vasoactive mechanism. Heart failure was the only cardiopulmonary event that occurred significantly more frequently with atrasentan than with placebo (6.7% vs 3%; P = .009) (Table 5). The median time to onset of heart failure was 47 days (range, 7-506 days). The overall incidence of cardiopulmonary events was low, and atrasentan-treated patients with heart failure tended to be older and had a history of significant cardiac disease compared with atrasentan-treated patients who did not experience heart failure (P ≤ .05). No atrasentan-treated patient died from heart failure or myocardial infarction. Aside from an increased incidence of anemia in the atrasentan group, there were no statistically or clinically significant differences between the treatment groups in terms of hematology or laboratory data.
Table 5. Treatment-emergent Cardiopulmonary Events of Interest
P values for pairwise comparisons were determined using the Fisher exact test with a significance level of P < .05. The only statistically significant treatment group difference was for heart failure (pooled adverse events).
Arrhythmia includes pooled terms of arrhythmia, atrial fibrillation, atrial flutter, atrial tachycardia, bradycardia, cardiac flutter, extrasystoles, heart rate increased, heart rate irregular, palpitations, sinus arrhythmia, supraventricular tachycardia, tachycardia, and ventricular extrasystoles.
Heart failure includes pooled terms of cardiac failure, cardiac failure congestive, cardiogenic shock, left ventricular failure, pulmonary edema, and right ventricular failure.
Despite a demonstration of atrasentan's biologic activity in this randomized, placebo-controlled, multinational trial in patients with nonmetastatic HRPC, confirming earlier observations of its effects on PSA and biomarkers of bone disease, we were not able to demonstrate a significant treatment difference in TTP or survival. Treatment with atrasentan resulted in a significantly slower rate of PSA rise, a significant attenuation of BALP rise, and a trend toward a delay in the time to initial presentation with skeletal metastases. Although more patients on atrasentan than patients on placebo discontinued the study because of adverse events, the safety profile of atrasentan was consistent with that observed in earlier trials, primarily reflecting the vasodilatory effects of ETA receptor blockade, without evidence of cumulative toxicity or hematologic toxicity.
The obvious issue is why the effects of atrasentan on PSA, biomarkers of bone lesions, and the incidence of bone lesions did not translate into a significant effect on the disease course and a delay in TTP. Atrasentan did demonstrate a favorable prolongation of TTP among patients at sites outside the US—representing the majority of patients enrolled in the study—whereas it did not delay TTP among US patients. Discontinuation for reasons other than disease progression was notably high in this trial. Nearly 30% of all patients discontinued treatment prematurely, and the percentage of patients on atrasentan that discontinued for reasons other than disease progression was significantly greater than the percentage of patients on placebo. A high premature discontinuation rate was reported previously in a multicenter trial that enrolled patients with nonmetastatic HRPC.22 In that trial, from 33% to almost 50% of patients in both treatment groups (placebo or sodium clodronate) discontinued prematurely and did not complete the 5-year treatment regimen. The most frequently cited reasons for premature discontinuation included adverse events and patient choice.
In the current trial, premature discontinuations were almost twice as frequent at US sites than at non-US sites. Cumulative discontinuation rates were higher for both treatment groups at US sites compared with non-US sites. Discontinuations because of adverse events also were more frequent at US sites and were more than twice as frequent among patients on atrasentan in both regions.
Are these observations merely the result of chance, or are they indicative of regional differences in patient populations or physician practice patterns? Regional differences in response were anticipated on the basis of results from earlier studies with atrasentan. The regional differences for placebo patients in both TTP and discontinuation rates were minimal, suggesting that differences in patient populations in the 2 regions were not a major factor. In contrast, a shorter median duration of treatment was observed for both treatment groups at US sites compared with non-US sites. Regional differences in physician practice patterns may have contributed to observed differences in treatment duration. At US sites, a shorter median duration of treatment was observed for both treatment groups compared with non-US sites. Another regional difference was in PSA levels at the time of premature discontinuation. It is noteworthy that, whereas the percentage of patients that discontinued prematurely because of PSA progression was similar for both treatment groups overall, the mean increase in PSA from the penultimate to the last visit and the mean PSA value at the last visit were lower at US sites than at non-US sites (Table 3). These data suggest that physicians and/or patients were more inclined toward premature discontinuation at US sites than at non-US sites. Alternative treatment options may have been more available at US sites, but whether this contributed to differences in treatment duration or to the incidence of premature discontinuation is merely speculative.
The safety profile observed for atrasentan in this trial was consistent with observations in previous trials and its mechanism of action as a selective ETA receptor antagonist. The overall incidence of cardiopulmonary events was low, and the only cardiopulmonary event that was significantly more common in patients on atrasentan than in patients on placebo was heart failure. Among atrasentan-treated patients, those with heart failure tended to be older and had a history of significant cardiac disease. The low incidence of hematologic toxicity observed with atrasentan treatment supports its use in combination with chemotherapy agents that affect hematologic parameters, such as docetaxel.
Atrasentan treatment did demonstrate some biologic activity, as evidenced by its effects on biomarkers of disease progression. Significant differences from placebo in PSA doubling time and changes in BALP levels were observed with atrasentan treatment. Effects on bone lesions also were observed, with a median delay of approximately 250 days in initial presentation of skeletal metastases with atrasentan. Among patients with confirmed disease progression, fewer were treated with atrasentan (48.6%) than with placebo (56.3%), and new skeletal metastases were cited as the primary disease progression event in a smaller percentage of patients in the atrasentan arm (36.2%) than patients in the placebo arm (44.3%). These observations of the effects of atrasentan on bone and bone markers were consistent with preclinical findings and with reports from phase 2 and 3 clinical trials.15–17, 23 The favorable effects of atrasentan on PSA also were consistent with observations from other clinical trials.
The suggestion of biologic activity, especially relevant to bone metastases, and the acceptable safety profile of atrasentan, particularly the lack of hematologic toxicity, warrant further evaluation of atrasentan, especially in combination with chemotherapy agents in prospective, randomized, controlled trials. Once such trial, sponsored by the Southwest Oncology Group (SWOG-0421), is ongoing in patients who have HRPC with bone metastases to evaluate the efficacy of the combination of atrasentan and docetaxel.
We thank Rachelle Weiss, PhD, and Sarah Duban, MA, ELS, for their excellent assistance in preparing this article.