Prognostic Models of Clinical Outcomes In Men With Castration Resistant Prostate

描述(申请人提供)：治疗男性去势抵抗前列腺癌(CRPC)的两难境地不仅在于疾病的异质性，还在于患有该疾病的患者的谱系。相当多的精力致力于了解肿瘤的异质性，并开发临床结果的预后模型，预测那些化疗不成熟的CRPC患者的临床结果。然而，在一线化疗失败的男性CRPC患者中，临床结果的预后因素的鉴定尚未得到调查。由于大量患者不仅一线化疗失败，而且由于多西紫杉醇的过度毒性，这种识别变得越来越重要。我们预计，随着更多有关患者病情的预后信息的积累，同一患者在其护理路径的不同阶段可能需要不同的模型(预后计算器)。这项建议的具体目标是：1)开发一种预测一线化疗失败的男性CRPC患者总存活率(OS)的预后模型。将使用独立的数据集验证该模型的预测准确性。2)建立预测一线化疗失败的CRPC患者无进展生存(PFS)的预后模型。将使用独立的数据集验证该模型的预测准确性。3a)确定卡巴紫杉醇治疗3个月后前列腺特异性抗原(PSA)下降30%是否为OS的有效替代标记物。卡巴西紫杉醇是FDA批准用于治疗一线化疗失败的男性的唯一药物。3b)建立和验证一个预测治疗后PSA下降的预测模型(3个月时E30%的下降)。4)使用Tropic试验检验进展时间与OS之间的相关性。创新：这项研究具有高度的创新性，因为它具有对未来PC试验的设计和进行产生积极影响的强大潜力。特别是，这项研究将是第一个确定和验证临床结果模型的研究，并将纳入两个最大的III期试验的数据，这些试验对晚期CRPC患者一线化疗失败的男性进行了研究。对于越来越多接受一线化疗并正在考虑二次化疗的男性来说，这些模型是完全不存在的。这些模型的开发将促进与CRPC患者的讨论，并有助于将这些模型整合到PC和患者护理的新临床试验的设计、实施和分析中。

DESCRIPTION (provided by applicant): The dilemma in treating men with castration resistant prostate cancer (CRPC) lies not only in the heterogeneity of the disease but also the spectrum of patients that have the disease. Considerable energy has been dedicated to understanding tumor heterogeneity and developing prognostic models of clinical outcomes in men with CRPC who are chemotherapy naive. The identification of prognostic factors of clinical outcomes in men with CRPC who failed frontline chemotherapy has not, however, been investigated. Such identification is increasingly important due to the large number of patients who not only fail frontline chemotherapy but have excessive toxicity due to docetaxel. We anticipate that the same patient may need different models (prognostic calculators) at different stages of their care pathway as more prognostic information on that person's condition accumulates. The specific aims in this proposal are: 1) to develop a prognostic model that will predict overall survival (OS) in men with CRPC who failed first line chemotherapy. The model will be validated for predictive accuracy using an independent dataset. 2) To develop a prognostic model that will predict progression-free survival (PFS) in CRPC men who failed first line chemotherapy. The model will be validated for predictive accuracy using an independent dataset. 3a) To determine if e 30% decline in prostate specific antigen (PSA) at 3-months following treatment with cabazitaxel, the only FDA approved drug for treating men who failed frontline chemotherapy, is a valid surrogate marker of OS. 3b) to develop and validate a prognostic model that will predict post-therapy decline in PSA (e30% decline from baseline at 3-months). 4) To test for the dependence between time to progression and OS using the TROPIC trial. Innovation: This study has a high degree of innovation because of its strong potential to positively impact the design and conduct of future trials in PC. In particular, this study will be the first to identify and validate models of clinical outcomes and will incorporate data from the two largest phase III trials of men with advanced CRPC who failed frontline chemotherapy. These models are completely absent for the growing group of men who have received frontline chemotherapy and are considering secondary chemotherapy. The development of these models will facilitate discussions with CRPC patients, as well as help integrate these models into the design, conduct and analysis of new clinical trials in PC and patient care.