When is radium 223 (Radium-223) preferred over Lutetium-177 (LU-177) in prostate cancer patients with PSMA (Prostate-Specific Membrane Antigen) expression and symptomatic bone metastases?

When to Use Radium-223 Instead of LU-177 in PSMA-Positive Prostate Cancer

Radium-223 should be used instead of LU-177-PSMA in patients with symptomatic bone metastases without visceral disease, especially when PSMA expression is low or heterogeneous. 1

Key Indications for Radium-223

Radium-223 is specifically indicated in the following scenarios:

1. Symptomatic bone metastases without visceral involvement

   • FDA-approved for patients with symptomatic bone metastases and no known visceral metastatic disease 1
   • Category 1 recommendation for patients with symptomatic bone metastases without visceral disease 1

2. Bone-predominant disease pattern

   • Most appropriate for patients with multiple bone metastases (at least two) 1
   • Particularly effective when bone is the primary site of metastatic burden 1

3. PSMA expression considerations

   • When PSMA expression is heterogeneous or low in bone metastases
   • When PSMA-negative bone lesions are present (as these would not respond to LU-177)

4. Prior treatment history

   • Can be used regardless of prior docetaxel exposure 1
   • Appropriate for patients who have failed or are unfit for docetaxel chemotherapy 1

Mechanism of Action Differences

Radium-223 works differently from LU-177-PSMA:

• Radium-223: Alpha-emitting radiopharmaceutical that mimics calcium and targets areas of increased bone turnover, regardless of PSMA expression 1
• LU-177-PSMA: Beta-emitting radiopharmaceutical that specifically targets PSMA-expressing tumor cells 1

Efficacy Considerations

Radium-223 has demonstrated:

• Improved overall survival (median 14.9 vs 11.3 months compared to placebo) 1
• Delayed time to first skeletal-related event (median 15.6 vs 9.8 months) 1
• Improved quality of life and reduced pain in patients with symptomatic bone metastases 1

Safety Profile

Radium-223 has a favorable toxicity profile:

• Low rates of grade 3-4 hematologic toxicity (3% neutropenia, 6% thrombocytopenia, 13% anemia) 1
• Short range of radioactivity limits damage to surrounding healthy tissue 1
• Primarily fecal elimination with mild non-hematologic side effects (nausea, diarrhea, vomiting) 1

Important Considerations and Precautions

1. Bone-protecting agents required

   • All patients receiving radium-223 should be given concomitant denosumab or zoledronic acid to prevent fractures 1
   • The PEACE III trial showed significantly higher fracture rates without bone-protecting agents (45.9% vs 2.8% with protection) 1

2. Combination therapy limitations

   • Should not be combined with docetaxel due to potential for additive myelosuppression 1
   • Not recommended for combination with abiraterone (based on ERA-223 trial results) 1

3. Monitoring requirements

   • Hematologic evaluation should be performed before treatment initiation and before each subsequent dose 1

Sequential Therapy Considerations

Recent research suggests that sequential therapy may be feasible:

• LU-177-PSMA after radium-223 appears to be well-tolerated with acceptable toxicity profiles 2, 3
• Patients with low bone tumor burden (2-20 lesions) may have better outcomes with sequential therapy than those with high tumor burden 3

Decision Algorithm

1. First, assess metastatic pattern:

   • If bone-predominant with symptomatic bone metastases and no visceral disease → Consider radium-223
   • If widespread metastases including visceral disease → LU-177-PSMA is preferred

2. Next, evaluate PSMA expression:

   • If high and homogeneous PSMA expression across all lesions → LU-177-PSMA may be more effective
   • If heterogeneous PSMA expression or PSMA-negative bone lesions → Radium-223 may be preferred

3. Consider patient symptoms:

   • If bone pain is the predominant symptom → Radium-223 has demonstrated efficacy for pain relief
   • If asymptomatic or minimally symptomatic → LU-177-PSMA may be preferred

4. Assess prior treatments:

   • Radium-223 is appropriate regardless of prior docetaxel use
   • LU-177-PSMA is indicated after both androgen receptor-directed therapy and taxane-based chemotherapy