Armstrong Andrew J, Febbo Phillip G
Department of Medicine and Surgery, Duke Comprehensive Cancer Center, Durham, NC 27710, USA.
Oncologist. 2009 Aug;14(8):816-27. doi: 10.1634/theoncologist.2009-0043. Epub 2009 Aug 14.
Recurrent prostate cancer has a complex molecular etiology and a prolonged disease course. Although initially responsive to androgen ablation, many men eventually become castration resistant, develop skeletal metastases, and are palliatively treated with docetaxel-based chemotherapy, radiation therapy, bisphosphonates, and best supportive care. Given the modest success rates of the current standard of care, clinical trial enrollment is encouraged. Castration-resistant prostate cancer (CRPC) is a heterogeneous disease, both in clinical manifestations and outcomes, requiring an individualized approach to both patient care and trial design. Herein, we review surrogate markers of disease progression and treatment efficacy in advanced prostate cancer in light of recently published guidelines that have redefined eligibility, response criteria, and suitable endpoints in prostate cancer drug development. The guidelines have refined outcome measures to potentially better capture clinical benefit and the ability of novel targeted molecular and biologic agents to impact favorably on this disease. We consider prostate-specific antigen changes, circulating tumor cells, bone scan alterations, markers of bone metabolism (urinary N-telopeptide and bone-specific alkaline phosphatase), pain improvements, and progression-free survival. To illustrate the role and challenges of these potential biomarkers and endpoints in drug development, we discuss a class of novel molecularly targeted agents, the src kinase inhibitors. Given that there are currently no validated surrogate markers of overall survival for assessing early clinical benefit from systemic therapy in metastatic CRPC, incorporation of relevant biomarkers into all phases of clinical development is essential to accelerate drug development in this field.
复发性前列腺癌具有复杂的分子病因和漫长的病程。尽管最初对雄激素剥夺治疗有反应，但许多男性最终会发展为去势抵抗性前列腺癌，出现骨转移，并接受以多西他赛为基础的化疗、放射治疗、双膦酸盐治疗以及最佳支持治疗。鉴于当前标准治疗的成功率有限，鼓励进行临床试验入组。去势抵抗性前列腺癌（CRPC）在临床表现和预后方面都是一种异质性疾病，需要针对患者护理和试验设计采取个体化方法。在此，我们根据最近发布的指南回顾晚期前列腺癌疾病进展和治疗疗效的替代标志物，这些指南重新定义了前列腺癌药物开发的入选标准、反应标准和合适的终点。这些指南完善了结局指标，以潜在地更好地捕捉临床获益以及新型靶向分子和生物制剂对该疾病产生有利影响的能力。我们考虑前列腺特异性抗原变化、循环肿瘤细胞、骨扫描改变、骨代谢标志物（尿N-端肽和骨特异性碱性磷酸酶）、疼痛改善情况以及无进展生存期。为了说明这些潜在生物标志物和终点在药物开发中的作用和挑战，我们讨论一类新型分子靶向药物，即src激酶抑制剂。鉴于目前尚无用于评估转移性CRPC全身治疗早期临床获益的总生存期的经过验证的替代标志物，将相关生物标志物纳入临床开发的各个阶段对于加速该领域的药物开发至关重要。
