A Phase I-II Study of Docetaxel and Atrasentan in Men with Castration-Resistant Metastatic Prostate Cancer

Abstract

Purpose: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer. Experimental Design: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m 2 every 21days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity. Results:Thirty-one patients were enrolled over three docetaxel dose levels (8 at . Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95 % CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy. Conclusions:The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m 2 . Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.Despite recent favorable declines in prostate cancer mortality, prostate cancer in 2008 remains a common cause of cancer death worldwide (1). Docetaxel and prednisone was U.S. Food and Drug Administration approved in 2004 for the palliative management of men with castration-resistant metastatic prostate cancer, based on improved survival, pain, and qualityof-life responses and tolerability compared with mitoxantrone and prednisone (2). As a result of this clinical activity in men with metastatic castration-resistant prostate cancer, docetaxel has become the standard by which experimental therapeutics are being compared against or added to, with the intent of improving on both quantity and quality of life for men with advanced prostate cancer.Prostate cancer commonly metastasizes to bone, using a number of homing receptors and signaling molecules to interact, adapt to, and grow in this microenvironment (3). One such paracrine and autocrine signaling molecule that plays an important role in metastatic prostate cancer progression is endothelin (4 -6). Endothelin-1 levels are increased in advanced prostate cancer and endothelin-1 acts as a mitogen for osteoblasts and prostate cancer cells through its interaction with the endothelin-A receptor (4). In addition to its proangiogenic and vasoconstricting activities important in the maintenance of vasomotor tone, endothelin additionall...

Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

“…Additional trials involving atrasentan in combination with docetaxel are ongoing. 37 Because significant questions remain about both the mechanism(s) by which ET-1 may be involved in prostate cancer progression and the clinical utility of ETA-selective antagonists in metastatic prostate cancer, we undertook a preclinical evaluation of atrasentan in a mouse model of prostate cancer metastatic osteoblasts to promote bone formation, a process which in turn promotes a microenvironment conducive for tumor growth. 18 This suggests that ETA on osteoblasts is a key therapeutic target and that ETA blockade is likely to specifically affect bone metastases, but not growth at other organ sites.…”

Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer

“…10 Encouraging preclinical data and initial clinical evidence supported investigation of zibotentan in combination with docetaxel in the phase III setting; [11][12][13][14] however, ENTHUSE M1C failed to confirm superiority for the zibotentan and docetaxel combination in mCRPC. 15 Collectively, results from the ENTHUSE programme, while disappointing, are consistent with those of the selective ET A receptor antagonist atrasentan, which produced positive phase II data, 11,16,17 but which also failed to significantly impact disease progression in the phase III setting. [18][19][20] Zibotentan was generally well tolerated in this patient population, with observed safety and tolerability data consistent with the known profile of zibotentan.…”

New Strategies for Medical Management of Castration-Resistant Prostate Cancer

“…Importantly, TTP results were consistent for the placebo arm worldwide [47]. A phase I–II trial of atrasentan 10 mg combined with docetaxel established the maximal tolerated dose of docetaxel to be 70–75 mg/m 2 [48]. A subsequent phase III trial (NCT00134056) comparing docetaxel and prednisone plus or minus atrasentan 10 mg has completed patient accrual with the primary outcome measurements of overall survival and PFS, but data are not yet mature.…”