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

Carducci, Michael A.; Padley, Robert J.; Breul, Jürgen; Vogelzang, Nicholas J.; Zonnenberg, Bernard A.; Daliani, Danai; Schulman, Claude; Nabulsi, Azmi A.; Humerickhouse, Rod; Weinberg, Mark; Schmitt, Jens; Nelson, Joel B.

doi:10.1200/jco.2003.04.176

Cited by 340 publications

(190 citation statements)

References 30 publications

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“…13 Among evaluable patients, there was a significant difference in time to progression between the 10-mg atrasentan group and the placebo group (196 days vs. 129 days, P ¼ .02). There was also a significant improvement in time to PSA progression (155 days vs. 71 days, P ¼ .002).…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Phase II studies in prostate cancer suggested that atrasentan had modest clinical activity, with statistically significant improvement in time to disease progression, time to prostatespecific antigen (PSA) progression, and changes in bone turnover markers compared with placebo. 9,13 Men with metastatic HRPC treated with placebo exhibited a continued increase in bone alkaline phosphatase (BAP), a marker of osteoblast activity, and N-telopeptide (NTX), a marker of osteoclast activity. Treatment with atrasentan blocked the increase in BAP and, to a lesser extent, attenuated the increase in NTX.…”

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confidence: 99%

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Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Michaelson

Kaufman

Kantoff

et al. 2006

Cancer

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BACKGROUND. Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin‐1 receptor, resulting in decreased osteoblast activity. METHODS. The effects of atrasentan alone versus combination therapy with atrasentan and zoledronic acid were investigated on bone turnover markers in men with bone metastases from prostate cancer. Forty‐four men were randomized to receive either atrasentan alone or combination therapy, and 33 completed at least 12 weeks of treatment and were included in the primary analysis. RESULTS. Treatment with the combination resulted in significantly lower serum levels of N‐telopeptide, a marker of bone resorption, compared with treatment with atrasentan alone. There was no difference between groups in serum levels of bone‐specific alkaline phosphatase, a marker of bone formation, at 12 weeks. Commonly observed adverse effects were edema, rhinitis, fatigue, and shortness of breath, most of which were NCI CTC (version 3.0) Grade 1. No Grade 4 or 5 treatment‐related toxicities were observed. There was minimal clinical efficacy, with no objective responses and only 1 prostate‐specific antigen (PSA) response. CONCLUSIONS. There is no evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers in men with metastatic prostate cancer. Cancer 2006. © 2006 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Michaelson

Kaufman

Kantoff

et al. 2006

Cancer

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“…a factor in tumor growth. Randomized placebo-controlled Phase II studies demonstrated a consistent ability of atrasentan to attenuate the increase in markers of prostate cancer progression such as prostate-specific antigen, alkaline phosphatase, Ntelopeptides, C-telopeptides, deoxypyridinoline, and lactate dehydrogenase (22)(23)(24). Phase III trials comparing atrasentan to placebo are nearing completion.…”

Section: Discussionmentioning

confidence: 99%

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

Ryan

Vogelzang

Vokes

et al. 2004

Clinical Cancer Research

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Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET A . Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.

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“…However, in common with other targeted therapies, and unlike cytotoxic therapies such as docetaxel, phase II data for atrasentan are consistent with cytostasis, leading to delays in progression rather than a reduction in tumour burden. 63 For the time being, the role of these agents remains in doubt as the results of phase III trials mature. Nonetheless, the eventual introduction of the new targeted therapies that are now in clinical development will be an important step in the management of HRPC.…”

Section: Future Directionsmentioning

confidence: 99%

The changing pattern of management for hormone-refractory, metastatic prostate cancer

James

Bloomfield

Luscombe

2006

Prostate Cancer Prostatic Dis

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Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormonerefractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy . Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway.

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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

Abstract: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Cited by 340 publications

References 30 publications

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

The changing pattern of management for hormone-refractory, metastatic prostate cancer

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