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

 描述（由申请人提供）：转移性去势难治性前列腺癌（CR-PC）患者预后不良，中位生存期约为14个月。10-20%的前列腺癌患者在初次诊断后5年内发生转移性CR-PC，因此需要改进的治疗策略。寡转移描述了一种转移数量有限的临床状态，各种寡转移性实体瘤的转移切除术可导致长期生存。立体定向消融放射治疗（SABR）是一种类似于手术的局部控制（LC）的无创治疗。根据我们的经验，少转移性前列腺癌患者（65%为CR-PC）在SABR治疗6个月时发生了100% LC，PSA相应下降。FDA批准11 C-胆碱PET/CT用于复发性转移性前列腺癌患者，先前的再分期研究已验证胆碱PET的灵敏度、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可能有助于识别“真正的”寡转移性CR-PC患者。目的/假设：11 C-胆碱PET/CT和SABR的组合可以改善“真正的”寡转移（CR-PC）患者的选择，改变他们的临床管理（即，从非治愈性到治愈性目的（添加SABR），并影响自然疾病进展（改善LC、PSA无进展生存期和总生存期[OS]）。SABR还可以诱导抗前列腺癌免疫，其可以用免疫调节抑制剂（例如，易普利姆玛，抗PD 1/PD-L1）。具体目标/研究设计：我们提出了一项前瞻性单臂II期临床试验，以评估11 C-胆碱PET/CT和SABR在转移性CR-PC患者中的作用，目的是改善临床结局（目的1）。我们还在目标2中提出了一项转化研究，以探索SABR治疗引起的诱导抗前列腺癌免疫。SABR诱导抗前列腺癌免疫的能力的证实将为联合收割机SABR和免疫调节剂（即，检查点抑制剂）在广泛的去势和化疗耐药转移性前列腺癌中的作用。提出的生物标志物（CD 11 ahighPD-1high CD 8 + T细胞）可能会改善对SABR和抗PD 1联合治疗的潜在应答者的识别。影响：11 C-胆碱PET/CT在选择其有限转移适合SABR的寡转移性CR-PC患者中的结合可以改善OS。如果我们的假设被证明是成功的，则这些患者的临床管理将出现范式转变（即，从非治愈性到治愈性）。SABR的抗前列腺免疫“原位”诱导，如果得到证实，将在未来的临床试验中形成SABR和免疫调节剂组合的强大理论基础。

 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.