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© 2003 American Society for Clinical Oncology Effect of Endothelin-A Receptor Blockade With Atrasentan on Tumor Progression in Men With Hormone-Refractory Prostate Cancer: A Randomized, Phase II, Placebo-Controlled Trial
From the Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University School of Medicine, Baltimore, MD; Abbott Laboratories, Abbott Park, IL; Urologische Klinik und Poliklinik, Klinikum rechts der Isar, Munich, Germany; Department of Medicine, Section of Hematology/Oncology and the Cancer Research Center, University of Chicago, Chicago, IL; Department of Medical Oncology, University Medical Center, Utrecht, the Netherlands; Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Department of Urology, University Hospital Erasme, Brussels, Belgium. Address reprint requests to Joel B. Nelson, MD, University of Pittsburgh School of Medicine, 5200 Centre Ave, Pittsburgh, PA 15232; email: nelsonjb{at}msx.upmc.edu.
Purpose: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. Patients and Methods: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. Results: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P = .13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P = .021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P = .002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. Conclusion: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.
IN THE United States, adenocarcinoma of the prostate is the second leading cause of cancer mortality in men.1 The predominant therapy for advanced disease is androgen suppression, an approach first described in 1941.2 Unfortunately, a central characteristic of prostate cancer is a propensity to become refractory to hormonal therapy. Median survival of men with metastatic, hormone-refractory prostate cancer is approximately 20 months,3 and death is typically preceded by painful, osteoblastic bone metastases.4,5 No approved therapeutic agent has yet prolonged survival or reliably delayed disease progression in these patients. The endothelin family of peptides has recently been identified as contributing to the pathophysiology of prostate cancer.6 The endothelins are paracrine/autocrine factors with diverse activity, and they modulate vasomotor tone, nociception, hormone production, and cell proliferation in a variety of tissues.7 These effects are mediated primarily by endothelin-1 (ET-1) through the endothelin-A (ETA) receptor.8 In the normal prostate gland, ET-19 is produced by epithelial cells and appears in high concentrations in seminal fluid.10 In prostate cancer, key components of the ET-1 clearance pathway, the endothelin-B (ETB) receptors, and the degradative enzyme neutral endopeptidase11 are diminished, resulting in an increase in local ET-1 concentrations. Expression of the ETA receptor also increases with tumor stage and grade in prostate cancer.12 There are multiple pathways by which the ET-1/ETA axis may promote prostate cancer progression. ET-1 is a mitogen for prostate cancer cell lines in vitro and acts synergistically with other peptide growth factors.13 ET-1 is also a mitogen for osteoblasts, the cell type pivotal in the hallmark osteoblastic response of bone to metastatic prostate cancer.6,14 Selective ETA-receptor antagonists block the proliferative effects of exogenous ET-1 in both prostate cancer cells and osteoblasts.13,15 In addition, ET-1 modulates apoptosis, nociception, and blood flow,8,16,17 indicating other potential benefits of ETA receptor antagonism in prostate cancer. Atrasentan (ABT-627) is a highly potent (Ki = 0.034 nmol/L) and selective (1,800-fold) ETA receptor antagonist that blocks or reverses the biologic effects of ET-1.18 In humans, atrasentan achieves physiologically active plasma concentrations when administered orally, once daily.19–21 We conducted a randomized, double-blind, placebo-controlled phase II trial to test the hypothesis that blockade of the ET-1/ETA receptor axis with atrasentan could delay the clinical progression of disease in men with hormone-refractory prostate cancer.
Eligibility Criteria Patients were required to have histologically documented adenocarcinoma of the prostate refractory to androgen ablation therapy (defined by a rise in prostate specific antigen [PSA] of at least 5 ng/mL or a PSA > 20 ng/mL on two occasions) and evidence of metastatic disease. Patients were also required to be free from opiate-requiring pain related to the disease, to have a score of 0 to 2 on the Eastern Cooperative Oncology Group Performance Status,22 and to have a life expectancy greater than 6 months. Patients were excluded if they had received radionuclides within 12 weeks of study entry, chemotherapy or an investigational drug within 4 weeks of study entry, or inadequate withdrawal from antiandrogen therapy. Adequate antiandrogen withdrawal was considered as follows: Subjects who had received flutamide had to have a documented minimum withdrawal period of 4 weeks with a documented subsequent rise in PSA after withdrawal of the antiandrogen on two consecutive measurements at least 1 month apart. Subjects who had received biclutamide or nilutamide had to have a documented minimum withdrawal period of 8 weeks with a documented subsequent rise in PSA, after withdrawal of the antiandrogen, on two consecutive measurements at least 1 month apart. Patients with metastases to the central nervous system or liver, a history of migraine or chronic headaches, or a known chronic infectious disease were also excluded.
Study Design
Outcome Measures The safety assessment of atrasentan was based on the evaluation of adverse events, vital sign measurements, and laboratory analyses. An independent data-monitoring committee regularly reviewed all safety data.
Statistical Analysis Two patient populations were defined for the statistical analyses. The intent-to-treat (ITT) population was defined as all randomly assigned patients. The assessable population was defined before unmasking of the study blind by excluding patients who did not meet study-defined PSA or antiandrogen withdrawal inclusion criteria, were taking excluded medications, received less than 50% of scheduled doses or fewer than 20 total doses, or initiated excluded medications during the study. Efficacy analyses were performed on both populations. Safety analyses were performed on the ITT population. Demographic variables were compared using Fisher’s exact tests for equality of proportions among groups and F-tests for equality of means among groups. Time-to-event analyses for time to progression and time to PSA progression were performed using Kaplan-Meier methodology and log-rank tests.25 Mean changes from baseline in biochemical markers were analyzed via analysis of covariance (ANCOVA), with treatment group as the factor and baseline values as the covariate. Fisher’s exact tests were used to compare frequencies of adverse events between treatment arms. Changes in laboratory values were summarized using National Cancer Institute Common Toxicity Criteria (NCI CTC) (version 1) or were rated as mild, moderate, or severe in the absence of NCI criteria. Quality-adjusted time to progression (QATTP) was determined by weighting the duration of time to progression (TTP) by a linear transformation of total and individual domain scores from both the EORTC QLQ-C30 and FACT-P instruments (Singh et al, manuscript in preparation).26–31 Median QATTP was estimated using Kaplan-Meier methodology, and the distributions of QATTP among treatment groups were compared using log-rank tests.
Disposition of Patients Of 365 prostate cancer patients screened for this study, 288 were randomly assigned (Fig 1  ). Baseline characteristics among the three groups were similar (Table 1). All groups had a high metastatic disease burden, as evidenced by elevated serum markers of PSA, alkaline phosphatase, acid phosphatase, and lactate dehydrogenase (LDH). Two hundred forty-four patients were evaluable, as determined before the unmasking of the blind. The reasons patients were unevaluable were well balanced across groups, with no statistically significant differences in progression rates found among the three groups of unevaluable patients (Fig 1).
During the course of the study, 41 patients withdrew before reaching a primary end point of disease progression: 10 for administrative reasons, 11 as a result of adverse events, and 18 for personal reasons; there were two deaths, which were included as events of disease progression. The other 39 patients were censored as of their last study visit. There were no statistically significant differences between groups in the frequencies or reasons for withdrawal.
Efficacy Analysis
The delay in disease progression was not statistically significant in the ITT analysis; however, in the assessable population (n = 244), median TTP was significantly prolonged in the 10-mg atrasentan group compared with the placebo group (196 days v 129 days; P = .021). A similar effect on median TTP was observed in the 2.5-mg atrasentan group compared with the placebo group (184 days v 129 days; P = .035; Fig 2B  ). Of placebo-treated patients, 35% were free from progression at 180 days compared with 53% and 54% in the 2.5-mg and 10-mg atrasentan groups, respectively (Table 2). The pattern of events representing disease progression was similar in the three treatment groups (Table 3).
In the ITT population, the secondary end point of PSA progression was statistically significant. Median time to PSA progression was twice as long in the 10-mg atrasentan group compared with the placebo group (155 days v 71 days; P = .002). Median time to PSA progression was longer in the 2.5-mg atrasentan group compared with the placebo group (141 days v 71 days; P = .055; Fig 3A ; Table 4).
In the assessable population, median time to PSA progression was also statistically significantly longer in the 10-mg atrasentan group compared with the placebo group (155 days v 71 days; P = .002; Fig 3B ). An effect of 10 mg atrasentan was apparent within 4 weeks of initiating treatment. Patients who received 2.5 mg atrasentan also exhibited a favorable trend in delay to PSA progression compared with the placebo group, although the delay initially observed was not maintained throughout the course of the study (P = .127).
Placebo-treated patients had significant and continued increases over baseline in serum LDH and acid phosphatase (markers of overall disease burden). In the ITT and assessable populations, elevation in LDH was uniformly attenuated by atrasentan (Table 5
Safety Analysis Safety analyses were performed on the ITT population. Headache (15% and 20%, 2.5-mg and 10-mg treatment groups, respectively), rhinitis (22% and 28%, 2.5-mg and 10-mg treatment groups, respectively), and peripheral edema (33% and 34%, 2.5-mg and 10-mg treatment groups, respectively) were the most common and statistically significant treatment-emergent adverse events associated with atrasentan therapy (Table 6 ). Most of the events were mild to moderate in severity, were similar across treatment groups, and responded to symptom-specific therapy when necessary. No patients discontinued the study because of headache or rhinitis. One patient discontinued the study with peripheral edema. This patient also had concurrent dyspnea. Dyspnea occurred more frequently in patients receiving 10 mg atrasentan than in placebo-treated patients (Table 6). The dyspnea events did not correlate with baseline cardiopulmonary status or change in physical exam and, in some cases, were associated with upper airway congestion. Infections were reported at a higher frequency in the 2.5-mg atrasentan group. Seventy percent of these events were associated with respiratory symptoms but did not require intervention. None of these events was associated with neutropenia or septicemia. No patients discontinued because of infection.
Mild but statistically significant decreases in blood pressure were observed in both atrasentan groups, compared with the placebo group, but no significant change in pulse rate was observed. The changes in blood pressure were most evident in patients who were hypertensive at baseline. There were no statistical differences between treatment groups in rates of hypotension or postural hypotension. Two patients in the 2.5-mg atrasentan group died during the study: one as a result of sudden death, and one because of an intracerebral hemorrhage. The investigator did not attribute the cause of death to study medication in either case.
Compared with baseline, patients in the 2.5-mg and 10-mg atrasentan groups had mean hemoglobin decreases of 0.9 ± 0.7 g/dL and 1.2 ± 0.7 g/dL, respectively (P
Quality of Life
This study demonstrates that the ETA receptor antagonist atrasentan has clinical activity in hormone-refractory prostate cancer. An ITT analysis demonstrated that patients treated with 10 mg atrasentan had a trend toward prolongation in disease progression and a statistically significant delay in PSA progression and attenuation of LDH and acid phosphatase. In addition, quality of life was maintained. In the assessable population that was defined before unmasking of the study blind, there was a significant delay in the primary end point of disease progression. These data substantiate the role of the ET-1/ETA axis as a growth and survival pathway and as a therapeutic target in hormone-refractory prostate cancer. ET-1 has pleiotropic effects in prostate cancer; thus, one or more mechanisms may explain the clinical activity of atrasentan. ET-1 directly stimulates prostate cancer growth in vitro and inhibits apoptosis of prostate cancer cells.6,32 These effects of ET-1 are blocked by selective ETA-receptor antagonists. ET-1 and ETA receptors are expressed by prostate cancer cell lines and in metastatic tumor specimens.12,13 ET-1 influences the interaction between tumor and bone, which may also contribute to the clinical benefit of atrasentan therapy. In prostate cancer, approximately 90% of patients have skeletal metastases at the time chemotherapy is initiated for the hormone-refractory state.5 These metastases are predominantly osteoblastic. ET-1 is both a potent mitogen for osteoblasts6,14 and an inhibitor of osteoclast motility and bone resorption, resulting in a net increase in new bone formation.33 Conditioned medium from ET-1-producing cell lines stimulated osteoblast proliferation and new bone formation; these effects were inhibited by selective ETA-receptor antagonists.34 In an osteoblastic murine model, overexpression of ET-1 increased, and a selective ETA antagonist decreased, new bone formation.15,34 Selective ETA-receptor antagonists also inhibit the development of bone metastases in nude mice inoculated with ET-1-producing human breast cancer cells.34 Atrasentan may inhibit tumor growth in bone both by direct effects on the tumor cells and by disrupting important bone-tumor interactions. The mechanism of action and side-effect profile of atrasentan differ substantially from agents that have shown promise in hormone-refractory prostate cancer. These agents include mitoxantrone5,35/glucocorticoids and the taxanes36,37 (both cytotoxic therapies). Headache, rhinitis, and peripheral edema were the most common side effects observed with atrasentan therapy. These side effects, which are attributable to the vasoactivity of this class of compounds, were mild to moderate in intensity, reversible, and readily controlled with symptomatic treatment. This profile may prove beneficial in future trials combining atrasentan with other cytotoxic therapies or bone-directed therapies such as bisphosphonates. A mild hemodilution effect was observed as a decrease in hemoglobin concentration, with corresponding decreases in hematocrit and RBC concentrations. With the observed safety profile and the potential to delay PSA and skeletal metastases progression, atrasentan may also be useful in earlier stages of prostate cancer, particularly when local therapy has failed or is at high risk of failing. The endothelin axis may also play a role in the pathogenesis of other malignancies. Expression of ET-1 and/or ETA receptors has been observed in ovarian, cervical, brain, breast, colon, liver, endometrial, pancreatic, and kidney cancers.38–43 In primary cultures of ovarian tumor cells, ET-1 stimulated cell proliferation and enhanced the mitogenic effect of epidermal growth factor.44 Clinical investigation of atrasentan in these cancer types is warranted. Forty-four patients did not meet eligibility criteria or did not follow protocol guidelines, a limitation of the study. Two hundred forty-four patients were ultimately assessable. Statistically significant differences between placebo and the higher dose of atrasentan were found with regard to both time to progression and time to PSA progression. However, in the ITT analysis, the statistically significant differences disappeared despite strong trends. It should be noted that exclusion of the 44 patients occurred before the study blind was broken. Hence, the potential of bias is likely minimal, given the consistency of the results when all patients’ responses are analyzed, particularly the effects of atrasentan on secondary end points. In addition, despite the specific exclusion of PSA progression as an end point, the knowledge of PSA values may have influenced investigators’ clinical evaluations and decisions. The limitations and potential biases of this trial have been addressed in the design of current phase III studies of atrasentan versus placebo in men with hormone-refractory prostate cancer. In conclusion, the selective endothelin-A-receptor antagonist, atrasentan, demonstrates evidence of activity in men with hormone-refractory metastatic prostate cancer. The safety profile is consistent with the pharmacologic activity of this class of compounds and is appropriate for a chronically dosed, noncytolytic therapy. Clinical investigation is warranted in earlier stages of prostate cancer and in other cancers for which the endothelin axis may be active. Phase III studies are currently under way to further evaluate the efficacy and clinical effectiveness.
In addition to the authors, the following investigators participated in the Atrasentan Clinical Research Group: C. Abbou, Créteil, France; P. Abrahamsson, Lund, Sweden; P. Alken, Mannheim, Germany; H. Bensadoun, Caen, France; M. Bidair, San Diego, CA; T. Billebaud, Créteil, France; J. Blom, Rotterdam, the Netherlands; P. Bollina, Edinburgh, United Kingdom; A. Borkowski, Warsaw, Poland; H. Botto, Suresnes, France; S. Brough, Crewe, United Kingdom; C. Buck, Glasgow, United Kingdom; J. Burgers, Columbus, OH; R. Castellanos, Fort Myers, FL; C. Chapple, Sheffield, United Kingdom; J. Chicharro, Malaga, Spain; N. Clarke, Manchester, United Kingdom; E. Cohen, La Jolla, CA; A. Dajani, Kleve, Germany; D. Dearnaley, London, United Kingdom; T. Demkow, Warsaw, Poland; P. Eisenberg, Greenbrae, CA; P. Ekman, Stockholm, Sweden; J. Ferrero, Nice, France; R. Fourcade, Auxerre, France; D. Gillatt, Bristol, United Kingdom; H. Graff, Solingen, Germany; J. Gschwend, Ulm/Donau, Germany; J. Gutheil, San Diego, CA; L. Harbach, San Diego, CA; C. Hernandez, Madrid, Spain; J. Hugosson, Gothenburg, Sweden; D. Jacqmin, Strasbourg, France; H. Jansen, Breda, the Netherlands; T Janus, North Chicago, IL; B. Jenkins, Cardiff, United Kingdom; A. Joyce, Leeds, United Kingdom; A. Kaisary, London, United Kingdom; W. Kessler, San Diego, CA; K. Klippel, Celle, Germany; K. Kurth, Amsterdam, the Netherlands; P. Laguna, Ciudad Real, Spain; O. Leiva Galvis, Madrid, Spain; J.L. Matych, Lodz, Poland; T. McNicholas, Stevenage, United Kingdom; G. Mickisch, Rotterdam, the Netherlands; E. Miekos, Lodz, Poland; K. Miller, Berlin, Germany; L. Moffat, Aberdeen, United Kingdom; G. Murphy, Seattle, WA; D. Neal, Newcastle, United Kingdom; S. Roth, Wuppertal, Germany; J. Salvatore, Mesa, AZ; J. Sarramon,Toulouse, France; P. Schellhammer, Norfolk, VA; W. Schulze-Seeman, Freiburg, Germany; S. Shah, Bradford, United Kingdom; R. Smith, Chula Vista, CA; E. Solsona, Valencia, Spain; H. Sommerfeld, Herne, Germany; M. Speakman, Taunton, United Kingdom; J. Valvo, Rochester, NY; R. Van Velthoven, Brussels, Belgium; H. Villavicencio, Barcelona, Spain; J. Waxman, London, United Kingdom; L. Weissbach, Berlin, Germany; M. Wirth, Dresden, Germany; F. Wolk, Torrance, CA
We thank the patients and health-care providers who participated in this clinical trial.
Supported by a grant from Abbott Laboratories, Abbott Park, IL. N.J. Vogelzang was supported in part by grant no. P30-CA-14599 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD. M.A. Carducci and J.B. Nelson were supported in part by NIH/NCI grant no. K08-CA-69164 from the National Cancer Institute, National Institutes of Health, and by the Association for the Cure of Cancer of the Prostate, Santa Monia, CA.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% over baseline), bone scan changes, and changes in bone and tumor markers.
.05 was considered to indicate statistical significance. 
