What is the recommended treatment approach for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have high Prostate-Specific Membrane Antigen (PSMA) expression but low Prostate-Specific Antigen (PSA) expression?

Treatment Approach for mCRPC with High PSMA and Low PSA Expression

For patients with metastatic castration-resistant prostate cancer (mCRPC) who have high PSMA expression but low PSA expression, 177Lu-PSMA-617 therapy is the recommended treatment option, particularly after progression on androgen receptor pathway inhibitors and taxane-based chemotherapy.

Significance of High PSMA/Low PSA Profile

High PSMA expression with low PSA expression represents a unique phenotype in mCRPC with important treatment implications:

• PSMA (Prostate-Specific Membrane Antigen) is a transmembrane protein highly expressed in prostate cancer cells, particularly in metastatic and castration-resistant disease
• Low PSA (Prostate-Specific Antigen) despite disease progression suggests a more aggressive, dedifferentiated tumor biology
• This discordance indicates that PSA alone may not accurately reflect disease burden or progression in these patients

Diagnostic Approach

1. PSMA PET/CT imaging:

   • Essential for confirming high PSMA expression
   • Options include Ga-68 PSMA-11, F-18 piflufolastat PSMA, or F-18 flotufolastat PSMA 1
   • Superior to conventional imaging for identifying metastatic sites with higher specificity and sensitivity

2. Exclusion of PSMA-negative lesions:

   • Critical to rule out PSMA-negative metastases that would not respond to PSMA-targeted therapy
   • FDG-PET may be considered to identify PSMA-negative/FDG-positive disease

Treatment Algorithm

First-line options for mCRPC:

1. If not previously received:
   • Androgen receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide, or darolutamide) 2
   • Docetaxel chemotherapy 2, 3

Second-line options after progression:

1. 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) 2, 1, 4
   • Demonstrated significant overall survival benefit (15.3 vs 11.3 months) and progression-free survival benefit (8.7 vs 3.4 months) compared to standard of care 4

2. Alternative options if 177Lu-PSMA-617 is not available or contraindicated:

   • Cabazitaxel chemotherapy (particularly after docetaxel failure) 2, 5
   • Olaparib for patients with BRCA1/2 mutations 2

Monitoring Treatment Response

For patients with low PSA expression, conventional PSA monitoring may be inadequate:

• Imaging-based assessment: PSMA PET/CT at 8-12 weeks after completion of therapy 1
• Clinical evaluation: Pain reduction and quality of life measures
• Regular monitoring of hematological parameters (hemoglobin, platelets, leukocytes) before each cycle 1

Management of Side Effects

177Lu-PSMA-617 therapy has specific toxicity concerns:

• Hematological toxicities: Grade 3-4 thrombocytopenia (13%), anemia, and lymphopenia 1, 4
• Common side effects: Fatigue, dry mouth, and nausea 1, 6
• Supportive care: Adequate hydration and balanced nutrition 1

Caveats and Considerations

• Approximately 30% of patients may be short or non-responders to 177Lu-PSMA therapy 7
• The discordance between PSMA and PSA expression may affect how treatment response is monitored
• Low PSA despite high disease burden may indicate more aggressive disease biology requiring closer monitoring

Future Directions

• Targeted alpha therapy using PSMA ligands (e.g., 225Ac-PSMA) may offer additional benefits for patients with high PSMA expression 7
• Earlier use of 177Lu-PSMA therapy in the disease course is being investigated, including in hormone-sensitive metastatic disease 8

This treatment approach leverages the high PSMA expression regardless of PSA levels, potentially offering improved outcomes for this specific subset of mCRPC patients.