What are the next steps in managing metastatic castration-resistant prostate cancer after completing 6 infusions of Pluvicto (lutetium-177 vipivotide tetraxetan)?

Treatment After Completing 6 Infusions of Pluvicto for Metastatic Castration-Resistant Prostate Cancer

After completing 6 infusions of Pluvicto (lutetium-177 vipivotide tetraxetan), the next treatment depends on disease response and progression status, but you should continue ADT indefinitely and consider cabazitaxel, abiraterone, or enzalutamide (if not previously used) as the next line of therapy. 1, 2

Critical First Step: Continue Androgen Deprivation Therapy

• You must continue ADT with an LHRH agonist or antagonist indefinitely to maintain castrate testosterone levels (<50 ng/dL), regardless of what additional therapy you choose next. 1, 2
• This is non-negotiable—all subsequent therapies are added on top of continued ADT, not as replacements. 2
• Verify testosterone remains <50 ng/dL through laboratory testing before proceeding with next-line therapy. 2

Assessment of Disease Status Post-Pluvicto

Evaluate treatment response using:

• PSA levels to assess biochemical response 1
• Imaging studies (CT, bone scan, or PSMA PET) to evaluate radiographic progression 1
• Performance status (ECOG score) to determine fitness for subsequent therapy 3
• Symptom burden, particularly bone pain requiring regular opiates 3

Treatment Algorithm Based on Performance Status

For Good Performance Status (ECOG 0-2)

If disease has progressed after Pluvicto, your treatment options in order of preference are:

1. Cabazitaxel + prednisone (if docetaxel was used before Pluvicto)

   • Provides median OS of 12.7 months with OS gain of 2.4 months (HR: 0.70) 1
   • This is the standard second-line chemotherapy after docetaxel failure 1
   • Monitor closely for neutropenia and gastrointestinal effects 1

2. Abiraterone + prednisone (if not previously used)

   • Provides OS gain of 4.6 months (HR: 0.74) after docetaxel failure 1
   • Can be used as second-line option if patient hasn't received it yet 1
   • Continue on top of ADT 2

3. Enzalutamide (if not previously used)

   • Provides OS gain of 4.8 months (HR: 0.53-0.75) after docetaxel therapy 1
   • Alternative androgen receptor pathway inhibitor if not used pre-Pluvicto 1
   • Continue on top of ADT 2

For Poor Performance Status (ECOG 3-4)

If performance status has declined to ECOG 3-4:

• Do not offer further anticancer treatment. 3
• Transition to palliative care with emphasis on quality of life and symptom management 3
• Treatment in this setting may delay access to end-of-life care and add unnecessary burden 3

Essential Molecular Testing

Before selecting next therapy, obtain:

• MSI/MMR testing to identify patients who may benefit from immunotherapy 1
• HRR gene mutation testing (BRCA1/2, ATM, etc.) to identify candidates for PARP inhibitors 1
• These targeted therapies should be prioritized if mutations are present 1

Monitoring During Subsequent Therapy

Implement structured monitoring to detect progression early:

• Regular PSA monitoring every 4-8 weeks 1, 4
• Imaging studies every 8-12 weeks or as clinically indicated 1
• Testosterone levels periodically to ensure castrate levels maintained 2
• Treatment-specific adverse events based on chosen therapy 1

Critical Pitfalls to Avoid

• Never discontinue ADT—this is the most common error and compromises all subsequent therapies 1, 2
• Do not repeat Pluvicto immediately—there is no established evidence for re-treatment with lutetium-177 PSMA-617 after completing 6 cycles 5, 6
• Do not use docetaxel rechallenge unless there was a prolonged response (>6 months) to initial docetaxel and progression occurred after switching to novel hormone therapy 1
• Avoid sequential androgen receptor pathway inhibitors (e.g., abiraterone after enzalutamide or vice versa) as cross-resistance is common, unless one was not used pre-Pluvicto 1

Special Considerations for Treatment Sequencing

The optimal sequence after Pluvicto is not established by randomized trials, but the NCCN framework suggests: 1

• If docetaxel → Pluvicto → consider cabazitaxel or unused AR pathway inhibitor
• If AR pathway inhibitor → docetaxel → Pluvicto → consider cabazitaxel or alternative AR pathway inhibitor (if not used)
• The goal is to ensure patients receive all available effective therapies sequentially to maximize overall survival 4

Emerging Options

• Actinium-225 PSMA radioligand therapy is mentioned as an emerging approach for PSMA-positive tumors, but is not yet guideline-recommended or FDA-approved 7
• Clinical trial enrollment should be strongly considered if available, as the treatment landscape continues to evolve rapidly 3