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.