Treatment Options for Advanced Disease

Introduction to Treatment Options

• The European Society for Medical Oncology recommends androgen receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide, or darolutamide) as first-line treatment for patients who have not previously received these treatments, with docetaxel chemotherapy also being a recommended first-line treatment option 1

First-Line Treatment

• Androgen receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide, or darolutamide) are recommended for patients who have not previously received these treatments, as suggested by the European Society for Medical Oncology 1
• Docetaxel chemotherapy is a recommended first-line treatment option, as stated by the European Society for Medical Oncology 1

Subsequent Treatment

• For patients with high PSMA expression who have progressed on AR pathway inhibitors and taxane chemotherapy, 177Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for 4-6 cycles) is recommended, as suggested by the European Society for Medical Oncology and the National Comprehensive Cancer Network (NCCN) 1, 2, 3, 4
• Cabazitaxel chemotherapy is an alternative option, particularly after docetaxel failure, as recommended by the European Society for Medical Oncology 1
• Olaparib is recommended for patients with BRCA1/2 mutations, as suggested by the European Society for Medical Oncology 1

Patient Selection for Lu-177 PSMA Therapy

• Eligible patients for Lutetium-177 (Lu-177) PSMA therapy include those with confirmed metastatic castration-resistant prostate cancer (mCRPC), high PSMA expression, and at least one PSMA-positive metastatic lesion, with previous treatment including at least one androgen receptor-directed therapy and one or two taxane-based chemotherapy regimens, as recommended by the National Comprehensive Cancer Network (NCCN) with a category 1 recommendation 3, 4
• Patients with confirmed mCRPC and high PSMA expression confirmed by PET imaging should be considered for treatment, as recommended by the Journal of Clinical Oncology and the National Comprehensive Cancer Network (NCCN) 2, 3, 4

Lu-177 PSMA Therapy Administration and Efficacy

• The standard dosage of Lu-177 PSMA therapy is 7.4 GBq (200 mCi) administered intravenously every 6 weeks for 4-6 cycles, as recommended by the National Comprehensive Cancer Network (NCCN) 3, 5, 6
• Lu-177 PSMA therapy has been shown to significantly improve overall survival (15.3 vs 11.3 months) and progression-free survival (8.7 vs 3.4 months) compared to standard of care alone in patients with mCRPC, with a PSA response rate of ≥50% observed in 57-66% of patients, as supported by the American Urological Association and the American Society of Clinical Oncology 3, 4, 5
• The following table summarizes the efficacy of 177Lu-PSMA-617 therapy:

3

Safety and Toxicity of Lu-177 PSMA Therapy

• Hematological toxicities, including Grade 3-4 thrombocytopenia (13% of patients), anemia, and lymphopenia, have been reported in patients receiving Lu-177 PSMA therapy, with common side effects also including fatigue, dry mouth, and nausea, and grade 3-4 adverse events occurring in 52.7% of patients receiving Lu-177 PSMA therapy compared to 38.0% with standard care alone 3, 4, 2
• Combination of Lu-177 PSMA therapy with abiraterone should be avoided due to increased fracture risk, as shown in the ERA 223 trial with radium-223 3

Imaging and Assessment

• Proper PSMA PET imaging is essential to confirm PSMA expression and rule out PSMA-negative lesions, with options including FDA-approved Ga-68 PSMA-11, as well as F-18 piflufolastat PSMA and F-18 flotufolastat PSMA due to equivalency reports, and is superior to conventional imaging for identifying sites of prostate cancer with higher specificity and sensitivity, according to the American College of Radiology 3, 4
• The optimal timeframe for assessment is 8-12 weeks after completion of therapy, allowing sufficient time for therapeutic effects to manifest, resolution of potential flare phenomenon, and accurate assessment of tumor response 7

Supportive Care

• A balanced diet that includes moderate red meat consumption (1-2 servings/week) is recommended to help improve blood counts in patients undergoing LU-177 infusions, as well as adequate hydration and a diet rich in vegetables and fruits to provide antioxidants and phytonutrients, and considering small, frequent meals to manage treatment-related side effects, as supported by the European Society for Medical Oncology, the American Institute for Cancer Research, the American Heart Association, the American College of Cardiology, and the European Association of Urology 8, 6, 9
• Regular assessment of hematological parameters (hemoglobin, platelets, leukocytes) is necessary before each cycle to monitor for toxicity, and radiation safety protocols must be followed to minimize exposure to others, as recommended by the National Comprehensive Cancer Network (NCCN) and the Prostate Cancer Clinical Trials Working Group (PCWG2) 10, 3, 6, 11