What is the efficacy of Alpha particle radio pharmaceuticals, such as Actinium-225 (Ac-225) labeled Prostate-Specific Membrane Antigen (PSMA), following 6 Lutetium-177 (LU-177) infusions for prostate cancer?

Efficacy of Alpha Particle Radiopharmaceuticals After 6 LU-177 Infusions for Prostate Cancer

Alpha particle radiopharmaceuticals such as Actinium-225 (Ac-225) PSMA can be highly effective in patients who have progressed after 6 cycles of Lutetium-177 PSMA therapy, with PSA response rates of approximately 65% even in heavily pretreated patients.

Alpha Radiopharmaceuticals vs. Beta Emitters

Alpha particle radiopharmaceuticals differ fundamentally from beta emitters like Lutetium-177:

• Alpha particles: Higher energy, shorter range (≤100 μm), higher linear energy transfer

  • Examples: Actinium-225 PSMA, Radium-223
  • Potentially more effective for micrometastatic disease and Lu-177-resistant tumors
  • More potent cell-killing ability due to double-strand DNA breaks

• Beta particles: Lower energy, longer range (average 0.7 mm), lower linear energy transfer

  • Examples: Lutetium-177 PSMA
  • Better for larger tumor volumes
  • Less radiation damage to surrounding tissues

Evidence for Alpha Particle Therapy After Lu-177 Failure

Actinium-225 PSMA Therapy

The most recent evidence shows that Ac-225-PSMA-617 demonstrates significant activity in patients who have progressed after Lu-177-PSMA therapy:

• Response rates: 65% of patients (17/26) achieved PSA decline ≥50% 1
• Survival metrics:
  • Median PSA progression-free survival: 3.5 months
  • Median clinical progression-free survival: 4.1 months
  • Median overall survival: 7.7 months 1
• Case reports: Complete responses have been documented in individual patients with metastatic castration-resistant prostate cancer who failed Lu-177-PSMA therapy 2

Radium-223

While not specifically studied after Lu-177 failure, Radium-223 is an established alpha-emitting radiopharmaceutical:

• Targets bone metastases specifically (calcium-mimetic properties)
• Improves overall survival in mCRPC with symptomatic bone metastases (median 14.9 vs 11.3 months) 3
• Not intended for use in combination with chemotherapy due to potential additive myelosuppression 3

Toxicity Profile of Alpha Particle Therapy

Alpha radiopharmaceuticals have distinct toxicity profiles that must be considered:

Actinium-225 PSMA

• Hematological toxicities (Grade 3/4):
  • Anemia: 35%
  • Leukopenia: 27%
  • Thrombocytopenia: 19% 1
• Xerostomia (dry mouth): All patients experience Grade 1/2, with 23% (6/26) discontinuing treatment due to this side effect 1

Radium-223

• Hematological toxicities (Grade 3-4):
  • Neutropenia: 2%
  • Thrombocytopenia: 3%
  • Anemia: 6% 3
• Non-hematological: Generally mild, including nausea, diarrhea, and vomiting 3

Emerging Combination Approaches

Research is exploring combination approaches to enhance efficacy:

• The AlphaBet trial is investigating the combination of Radium-223 and Lu-177-PSMA-I&T, hypothesizing that combining a bone-specific alpha-emitter with Lu-177-PSMA will improve eradication of micrometastatic osseous disease 4

Patient Selection Considerations

For optimal outcomes with alpha particle therapy after Lu-177 failure:

1. PSMA expression: Confirm persistent PSMA expression with appropriate imaging
2. Disease burden: Patients with liver metastases have significantly worse outcomes (median OS 4.3 vs 10.4 months) 1
3. Bone marrow function: Ensure adequate baseline hematologic parameters given the risk of myelosuppression
4. Salivary gland function: Consider baseline salivary gland function given the high risk of xerostomia with Ac-225 PSMA

Clinical Recommendation Algorithm

For patients who have progressed after 6 cycles of Lu-177 PSMA therapy:

1. If predominantly bone metastases with symptoms and no visceral disease:

   • Consider Radium-223 (category 1 recommendation) 3
   • Administer as 6 monthly intravenous injections

2. If PSMA-positive disease regardless of location:

   • Consider Ac-225-PSMA-617 (investigational)
   • Typical regimen: Every 8 weeks until progression or intolerable side effects
   • Median administered activity: 9 MBq per cycle 1

3. If poor bone marrow reserve:

   • Proceed with caution with either agent
   • Consider dose reduction or alternative approaches

Conclusion

Alpha particle radiopharmaceuticals represent a promising therapeutic option for patients who have progressed after Lu-177 PSMA therapy, with Ac-225 PSMA showing significant activity even in this heavily pretreated population. The higher potency of alpha emitters may overcome resistance mechanisms that develop after beta-emitter therapy, though at the cost of potentially increased toxicity, particularly xerostomia with Ac-225 PSMA therapy.