Supplementary Material for: Novel Combination of Metronomic Cyclophosphamide and Darolutamide Induces Sustained Clinical Response in Heavily Treated Prostate Cancer with Prostate-Specific Membrane antigen Negative Liver Metastases and Rapid Disease Progression

Introduction: Treatment options for refractory prostate-specific membrane antigen (PSMA)-negative liver metastases from metastatic castration-resistant prostate cancer (mCRPC) are limited and challenging. This case report presents our clinical observation of a sustained response to a novel combination of metronomic cyclophosphamide (mCyc) and darolutamide in a 65-year-old male with heavily treated PSMA-negative mCRPC with rapid disease progression.

Case Presentation: The patient was initially diagnosed four years prior to our evaluation with metastatic prostate cancer and treated with androgen deprivation therapy (ADT) with leuprolide, enzalutamide, and definitive external beam radiation therapy (EBRT) to prostate and pelvic lymphadenopathy, along with stereotactic body radiation to oligometastatic bone disease. Upon progression to mCRPC, he received abiraterone with prednisone followed by docetaxel with prednisone, both of which resulted in temporary disease stabilization but eventual rapid progression with deterioration in performance status. Given the lack of effective, tolerable options, a combination of mCyc and darolutamide was initiated. The patient demonstrated an impressive clinical response, including significant radiographic response in liver metastatic disease, 80% reduction in prostate-specific antigen (PSA) levels, and improved quality of life with resolution of all cancer related symptoms without significant treatment-related toxicities, with ongoing response at six months.

Conclusion: This report highlights the complex challenges of managing mCRPC with PSMA-negative liver metastases. mCyc with darolutamide may represent a valuable therapeutic option for elderly patients with multiple comorbidities who have exhausted standard treatment options. However, further research is needed to establish the efficacy and safety of this combination in broader populations.

引言：转移性去势抵抗性前列腺癌（mCRPC）伴难治性前列腺特异性膜抗原（PSMA）阴性肝转移瘤的治疗方案选择有限且极具挑战。本病例报告呈现了我们对一名65岁男性患者的临床观察结果，该患者经多线治疗后仍出现疾病快速进展，其转移性去势抵抗性前列腺癌呈PSMA阴性，对节拍式环磷酰胺（mCyc）联合达罗他胺的新型治疗方案产生了持续应答。

病例介绍：在本次评估的4年前，患者被确诊为转移性前列腺癌，初始接受了雄激素剥夺治疗（ADT）联合亮丙瑞林、恩扎卢胺，以及针对前列腺和盆腔淋巴结病变的根治性外照射放疗（EBRT），同时对寡转移性骨病实施了立体定向体部放疗。进展为转移性去势抵抗性前列腺癌后，患者先后接受了阿比特龙联合泼尼松、多西他赛联合泼尼松治疗，两种方案均仅实现了短暂的疾病稳定，但最终出现快速进展且体能状态恶化。鉴于缺乏有效且耐受良好的治疗方案，我们启动了节拍式环磷酰胺联合达罗他胺的联合治疗方案。患者展现出显著的临床应答：肝转移瘤影像学明显缓解，前列腺特异性抗原（PSA）水平降低80%，所有癌症相关症状均得到缓解，生活质量得以改善，且未出现显著的治疗相关不良反应，随访6个月时应答仍在持续。

结论：本报告凸显了管理PSMA阴性肝转移型转移性去势抵抗性前列腺癌的复杂挑战。节拍式环磷酰胺联合达罗他胺或许可为多线治疗耗尽、合并多种基础疾病的老年患者提供一种有价值的治疗选择。不过，仍需开展进一步研究以明确该联合方案在更广泛人群中的有效性与安全性。