Prognostic Models of Clinical Outcomes In Men With Castration Resistant Prostate

描述（由申请人提供）：治疗去势抵抗性前列腺癌（CRPC）男性的困境不仅在于疾病的异质性，还在于患有该疾病的患者谱。相当多的精力一直致力于了解肿瘤异质性和发展的临床预后模型与CRPC男性谁是化疗初治。然而，尚未研究一线化疗失败的CRPC男性患者临床结局的预后因素。由于大量患者不仅一线化疗失败，而且由于多西他赛而产生过度毒性，因此这种识别越来越重要。我们预计，同一个病人可能需要不同的模型（预后计算器）在不同阶段的护理途径，因为更多的预后信息，该人的条件积累。该提案的具体目的是：1）开发一种预后模型，预测一线化疗失败的CRPC男性患者的总生存期（OS）。将使用独立数据集验证该模型的预测准确性。2)开发一种预测一线化疗失败的CRPC男性患者无进展生存期（PFS）的预后模型。将使用独立数据集验证该模型的预测准确性。3a）确定卡巴他赛（FDA批准的唯一用于治疗一线化疗失败的男性的药物）治疗后3个月时前列腺特异性抗原（PSA）下降30%是否是OS的有效替代标志物。3b）开发并验证将预测治疗后PSA下降（3个月时从基线下降30%）的预后模型。4)使用TROPIC试验检验至疾病进展时间与OS之间的依赖性。创新：本研究具有高度的创新性，因为其对未来PC试验的设计和实施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局模型的研究，并将纳入两项最大的晚期CRPC男性患者一线化疗失败的III期试验的数据。这些模型对于越来越多的接受一线化疗并正在考虑二次化疗的男性来说完全不存在。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。 公共卫生相关性：对于已经接受一种化疗方案并正在考虑二次化疗的新兴男性群体，预后模型不可用。如果这些结果得到验证，我们的模型可以前瞻性地用于随机II期和III期试验，以确保评估的治疗组具有可比性。此外，它们可以帮助确定CRPC男性亚组，特别是好或差的治疗，随后可以定制。这些模型将作为预测工具，可以在临床实践中轻松快速地实施。

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. PUBLIC HEALTH RELEVANCE: Prognostic models are not available for the burgeoning group of men who have received one regimen of chemotherapy, and are considering secondary chemotherapy. If these results are validated, our models can be used prospectively in randomized phase II & phase III trials to ensure that the treatment groups being evaluated are comparable. Further, they can assist in identifying subgroups of men with CRPC with particularly good or poor prognoses for whom therapy can be subsequently tailored. These models will serve as prediction tools that can be easily and rapidly implemented in clinical practice.