Will Lutetium-177 (LU-177) PSMA-targeted radioligand therapy reduce prostate cancer that expresses Prostate-Specific Membrane Antigen (PSMA)?

Lutetium-177 PSMA Therapy for PSMA-Expressing Prostate Cancer

Lutetium-177 (Lu-177) PSMA therapy is highly effective for reducing prostate cancer that expresses PSMA, with significant improvement in overall survival (15.3 vs 11.3 months) and progression-free survival (8.7 vs 3.4 months) compared to standard of care alone. 1, 2, 3

Patient Selection Criteria

Lu-177 PSMA therapy is indicated for patients with:

• Confirmed metastatic castration-resistant prostate cancer (mCRPC)
• High PSMA expression confirmed by PET imaging
• At least one PSMA-positive metastatic lesion
• No dominant PSMA-negative metastatic lesions
• Previous treatment with:
  • At least one androgen receptor-directed therapy
  • One or two taxane-based chemotherapy regimens 1, 2

PSMA-negative lesions are defined as metastatic disease lacking PSMA uptake, including:

• Bone with soft tissue components ≥1.0 cm
• Lymph nodes ≥2.5 cm in short axis
• Solid organ metastases ≥1.0 cm in size 1

Treatment Protocol

• Standard dosage: 7.4 GBq (200 mCi) administered intravenously
• Treatment frequency: Every 6 weeks
• Treatment duration: 4-6 cycles 1, 2, 3

Efficacy

Lu-177 PSMA therapy demonstrates significant clinical benefits:

Outcome	Lu-177 PSMA + Standard Care	Standard Care Alone	Hazard Ratio	p-value
Median Overall Survival	15.3 months	11.3 months	0.62	<0.001
Median Progression-Free Survival	8.7 months	3.4 months	0.40	<0.001

Additional efficacy metrics:

• PSA response rate (≥50% decline): 56-57% of patients 2, 3, 4
• Objective response in measurable disease: 82% of patients 5
• Disease control rate: Significantly higher with Lu-177 PSMA 3

Safety Profile

Common adverse events include:

• Hematological toxicities:

  • Grade 3-4 thrombocytopenia: 13% of patients
  • Anemia, lymphopenia also reported 1, 2, 5

• Non-hematological toxicities:

  • Dry mouth (87% grade 1)
  • Fatigue (50% grade 1-2)
  • Nausea (50% grade 1-2) 2, 5

The incidence of grade ≥3 adverse events is higher with Lu-177 PSMA than standard care alone (52.7% vs 38.0%), but quality of life is not adversely affected 3.

Monitoring Recommendations

• Regular assessment of hematological parameters before each cycle
• PSA monitoring (evaluate response no earlier than 12 weeks after treatment initiation)
• Follow-up imaging to assess response 2

Clinical Considerations and Caveats

1. Patient selection is critical: Proper PSMA PET imaging is essential to confirm PSMA expression and rule out PSMA-negative lesions 1, 2

2. Predictors of better response:

   • Predominantly lymph node metastatic disease
   • Chemotherapy-naïve status
   • Lower baseline PSA levels 4

3. Imaging options: While FDA approved Ga-68 PSMA-11 for use with Lu-177 PSMA therapy, F-18 piflufolastat PSMA and F-18 flotufolastat PSMA can also be used due to equivalency reports 1

4. Emerging evidence: Early research suggests potential application in hormone-sensitive metastatic prostate cancer, though this remains investigational 6

5. Avoid combination with abiraterone: The ERA 223 trial showed increased fracture risk when radium-223 (another radiopharmaceutical) was combined with abiraterone 1

Lu-177 PSMA therapy represents a significant advancement for patients with PSMA-expressing metastatic castration-resistant prostate cancer who have progressed after conventional treatments, offering meaningful survival benefits with manageable toxicity.