A Phase II Evaluation of SABR in Oligometastatic Castration-Refractory Prostate Cancer and Immunogenicity of SABR

 描述(申请人提供)：转移性去势难治性前列腺癌(CR-PC)患者预后较差，中位生存期约14个月。10-20%的前列腺癌患者在初诊后5年内发展为转移性CR-PC，因此需要改进治疗策略。少转移是指转移数量有限的临床状态，各种少转移实体肿瘤的转移切除可导致长期生存。立体定向消融放射治疗(SABR)是一种局部控制(LC)的非侵入性治疗，类似于手术。根据我们的经验，少转移前列腺癌患者(65%为CR-PC)在接受SABR治疗的6个月时经历了100%的LC，同时他们的PSA也相应下降。11C-胆碱PET/CT被FDA批准用于复发转移性前列腺癌患者，先前的再分期研究证实，胆碱PET的敏感性、特异性、阳性预测值和阴性预测值分别为85-100%、76-96%、76-91%和81-100%。因此，~(11)C-胆碱PET/CT可能有助于鉴别“真正的”少转移CR-PC患者。目的/假设：11C-胆碱PET/CT和SABR的结合可以改善“真正的”少转移瘤(CR-PC)患者的选择，改变他们的临床治疗(即，随着SABR的加入，从无效变为治疗意图)，并影响自然疾病的进展(改善LC、PSA无进展生存期和总生存期[OS])。SABR还可诱导抗前列腺癌免疫，这种免疫可被免疫调节抑制剂(如ipilimumab、抗PD1/PD-L1)放大为长期保护性免疫。具体目标/研究设计：我们提出了一项前瞻性的单臂II期临床试验，评估11C-胆碱PET/CT和SABR在转移性CR-PC患者中的作用，目的是改善临床结果(目标1)。我们还建议在目标2中进行一项翻译研究，以探索SABR治疗诱导的抗前列腺癌免疫。SABR诱导抗前列腺癌免疫的能力的确认将为SABR与免疫调节剂(即检查点抑制剂)联合治疗广泛的去势和化疗耐药转移性前列腺癌提供强有力的理论基础。建议的生物标记物(CD11aHighPD-1高CD8+T细胞)可能会改善对SABR和抗PD1联合治疗的潜在应答者的识别。影响：将11C-胆碱PET/CT用于选择对SABR有局限性转移的少转移CR-PC患者，可能会改善OS。如果我们的假设被证明是成功的，这些患者的临床管理将会有一个范式的转变(即，从无治疗意图到治疗意图)。如果证实SABR“原位”诱导抗前列腺免疫，将为SABR和免疫调节剂在未来的临床试验中的结合提供强有力的理论基础。

 DESCRIPTION (provided by applicant): Metastatic castration-refractory prostate cancer (CR-PC) patients have poor prognosis with median survival of approximately 14 months. 10-20% of all prostate cancer patients develop metastatic CR-PC within 5 years of initial diagnosis, and therefore, improved therapeutic strategies are needed. Oligometastasis describes a clinical state where metastases are limited in number, and metastatectomies for various oligometastatic solid tumors can lead to long-term survival. Stereotactic Ablative Radiotherapy (SABR) is a noninvasive therapy with local control (LC) similar to surgery. In our experience, oligometastatic prostate cancer patients (65% were CR-PC) experienced 100% LC at 6 months with SABR with corresponding decline in their PSA. 11C-Choline PET/CT was FDA-approved in recurrent metastatic prostate cancer patients, and prior restaging studies have validated the sensitivity, specificity, positive predictive value, and negative predictive value of Choline PET at 85-100%, 76-96%, 76-91%, and 81-100%, respectively. Therefore, 11C- Choline PET/CT may help to identify "true" oligometastatic CR-PC patients. Objectives/Hypothesis: The combination of 11C-Choline PET/CT and SABR may improve "true" oligometastatic (CR-PC) patient selection, alter their clinical management (i.e., from noncurative to curative intent with the addition of SABR), and impact natural disease progression (improve LC, PSA progression-free survival and overall survival [OS]). SABR may also induce anti-prostate cancer immunity, which could be amplified into long-term protective immunity with immune-regulation inhibitors (e.g., ipilimumab, anti-PD1/PD-L1). Specific Aims/Study Design: We propose a prospective single arm phase II clinical trial to assess the role of 11C-Choline PET/CT and SABR in metastatic CR-PC patients with the goal of improving clinical outcomes (Aim 1). We also propose a translational study in Aim 2 to explore the induction anti-prostate cancer immunity elicited by SABR treatments. The confirmation of the ability of SABR to induce anti-prostate cancer immunity would provide a robust rationale to combine SABR and immunomodulating agents (i.e., checkpoint inhibitors) in widespread castration- and chemotherapy- resistant metastatic prostate cancer. The proposed biomarker (CD11ahighPD-1high CD8+ T cells) may improve identification of potential responders to the combined SABR and anti-PD1 therapy. Impact: The incorporation of 11C-Choline PET/CT in the selection of oligometastatic CR-PC patients whose limited metastases are amenable to SABR may improve OS. If our hypothesis is proven successful, there would be a paradigm shift in the clinical management of these patients (i.e., from noncurative to curative intent). The "in situ" induction of anti-prostate immunity by SABR, if confirmed, would form a robust rationale for the combination of SABR and immunomodulating agents in future clinical trials.