Abstract
Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.
Highlights
Prostate cancer is the most common non-cutaneous malignancy and the second leading cause of cancer deaths among men in the United States, with an estimated incidence of 241,740 new cases diagnosed and approximately 28,170 men expected to die of the disease in 2012 [1]
Similar disappointing results were reported that led to the termination of the late-stage trial of sunitinib, an antiangiogenic tyrosine kinase inhibitor (TKI), in combination with prednisone as second-line therapy for metastatic castration-resistant prostate cancer (mCRPC) patients due to the lack of overall survival (OS) prolongation, despite an improvement in progressionfree survival (PFS) (5.6 vs. 3.7 months; HR = 0.74; P = .0077) [22]
In order to achieve sustained success in drug development, researchers must remain conscious of the challenges and limitations in conducting clinical trials in prostate cancer
Summary
Prostate cancer is the most common non-cutaneous malignancy and the second leading cause of cancer deaths among men in the United States, with an estimated incidence of 241,740 new cases diagnosed and approximately 28,170 men expected to die of the disease in 2012 [1]. To overcome the hurdle of multiple pre-existing or induced pro-angiogenic factors, a strategy combining docetaxel with dual antiangiogenic agents with distinct anti-angiogenic properties, bevacizumab and thalidomide, represented a new approach, and was demonstrated in a phase II trial It resulted in high response rates in PSA changes and measurable diseases, and an encouraging estimated median survival rate in this patient population [58]. Perhaps a combination therapy that integrates uninterrupted androgen deprivation by a novel, potent agent like AA and cytotoxic agents with a proven survival benefit such as docetaxel or cabazitaxel, will likely provide synergistic clinical benefit and overcome resistance in mCRPC patients Such trials are currently underway in phase I testing (ClinicalTrials.gov NCT01400555, NCT01511536)
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