Does Lutetium-177 (Lu-177) kill all Prostate-Specific Membrane Antigen (PSMA)-positive types of prostate cancer?

Lutetium-177 Does Not Kill All PSMA-Positive Types of Prostate Cancer

Lutetium-177 PSMA therapy is not effective against all PSMA-positive prostate cancer types, with response rates showing that approximately 55-66% of patients experience a significant PSA decline of ≥50%, indicating that a substantial proportion of PSMA-positive tumors do not respond adequately to this treatment. 1, 2

Efficacy and Response Rates

Lu-177 PSMA therapy demonstrates variable effectiveness against PSMA-positive prostate cancer:

• The VISION trial showed that Lu-177 PSMA-617 prolonged overall survival (median 15.3 vs. 11.3 months) and imaging-based progression-free survival (median 8.7 vs. 3.4 months) compared to standard care alone 1
• PSA response rates (≥50% decline) range from approximately:
  • 44.9% in an Australian tertiary institution study 3
  • 57% in the LuPSMA phase 2 trial 2
  • Up to 66% in patients with confirmed mCRPC and high PSMA expression 4

These response rates clearly demonstrate that while Lu-177 PSMA therapy is effective for many patients, a significant percentage (approximately 34-55%) of PSMA-positive prostate cancers do not respond adequately to treatment.

Factors Affecting Treatment Response

Several factors may explain why Lu-177 does not kill all PSMA-positive prostate cancers:

1. Heterogeneity in PSMA Expression: Despite positive PSMA PET imaging, tumors may have variable PSMA expression levels across different metastatic sites 5

2. Patient Selection Criteria: Proper patient selection is critical and requires:

   • Confirmed metastatic castration-resistant prostate cancer (mCRPC)
   • High PSMA expression on PET imaging
   • No dominant PSMA-negative metastatic lesions 4

3. Primary Resistance: Some tumors exhibit primary resistance to Lu-177 PSMA therapy, which may be related to molecular characteristics not yet fully understood 5

4. Treatment History: Prior treatments may affect response to Lu-177 PSMA therapy, with most studies focusing on heavily pre-treated patients who have progressed after standard treatments 1, 2

Combination Approaches to Improve Efficacy

Recent research suggests that combination approaches may improve outcomes:

• Combining Lu-177 PSMA-617 with androgen receptor pathway inhibitors (ARPIs) significantly prolonged median progression-free survival compared to Lu-177 PSMA-617 alone (11 vs. 5.6 months) 6
• This combination approach may help overcome resistance mechanisms and improve response rates

Monitoring and Response Assessment

For patients undergoing Lu-177 PSMA therapy:

• PSA response should be evaluated no earlier than 12 weeks after treatment initiation 4
• Regular monitoring of blood counts is essential due to potential hematological toxicities 4
• Patients with PSA decline have significantly longer progression-free survival and overall survival compared to non-responders 4

Safety and Toxicity Profile

Common side effects of Lu-177 PSMA therapy include:

• Hematological toxicities (anemia, thrombocytopenia, lymphopenia)
• Fatigue, dry mouth, and nausea
• Grade 3-4 adverse events occur in approximately 52.7% of patients receiving Lu-177 PSMA therapy 4, 1

Clinical Implications

The incomplete response to Lu-177 PSMA therapy highlights the need for:

1. Better predictive biomarkers to identify which patients will benefit most from treatment 5
2. Combination strategies to improve efficacy 6
3. Sequential treatment approaches for patients with partial or no response
4. Continued research into resistance mechanisms and how to overcome them

In conclusion, while Lu-177 PSMA therapy represents an important advancement in the treatment of metastatic castration-resistant prostate cancer, it does not effectively kill all PSMA-positive cancer cells in all patients, with response rates indicating that a substantial proportion of patients experience limited or no benefit.