What is the most effective treatment for recurrent metastatic castration-resistant prostate cancer (CRPC) that generates Prostate-Specific Membrane Antigen (PSMA) and has progressed after two months of Androgen Deprivation Therapy (ADT) and apalutamide (Erleada)?

Treatment for Recurrent Metastatic Castration-Resistant Prostate Cancer with PSMA Expression After ADT and Apalutamide

Lutetium-177-PSMA-617 (177Lu-PSMA-617) is the most effective treatment for PSMA-positive metastatic castration-resistant prostate cancer that has progressed after ADT and apalutamide therapy. 1

Treatment Rationale

• 177Lu-PSMA-617 is specifically FDA-approved for adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (such as apalutamide) and taxane-based chemotherapy 1
• In the VISION trial, 177Lu-PSMA-617 demonstrated significant overall survival benefit with a median OS of 11.3 months and OS gain of 4.0 months (HR: 0.62) compared to standard of care 2
• The ESMO clinical practice guidelines assign 177Lu-PSMA-617 a high score (4m on Form 2a) for clinical benefit in this setting 2

Treatment Algorithm

First-line option after AR pathway inhibitor failure:

1. Docetaxel-based chemotherapy (if not previously received)
   • Demonstrated improved overall survival with median OS of 16.3 months (OS gain: 2.9 months; HR: 0.79) 2
   • Provides improved quality of life in the mCRPC setting 2
   • Standard regimen is every 3 weeks, with an alternative biweekly regimen option 2

Second-line options (after docetaxel):

1. 177Lu-PSMA-617 (preferred for PSMA-positive disease)

   • Most effective for patients with PSMA-positive mCRPC who have received both AR pathway inhibition and taxane-based chemotherapy 1
   • Provides significant survival benefit (HR: 0.62) 2

2. Cabazitaxel + prednisone

   • Effective after docetaxel failure with median OS of 12.7 months (OS gain: 2.4 months; HR: 0.70) 2
   • Particularly effective after AR pathway inhibitor failure (CARD trial showed PFS gain of 4.3 months; HR: 0.54) 2

3. Abiraterone + prednisone

   • If not previously used, provides OS gain of 4.6 months (HR: 0.74) after docetaxel failure 2
   • Requires monitoring for hypertension, hypokalemia, peripheral edema, and liver injury 2

4. Enzalutamide

   • If not previously used, provides OS gain of 4.8 months (HR: 0.53-0.75) after docetaxel therapy 2
   • Requires monitoring for fatigue, diarrhea, hot flashes, headache, and seizures (rare) 2

Special Considerations

• Molecular testing: Patients with mCRPC should undergo metastatic lesion biopsy with MSI/MMR testing and germline/tumor testing for mutations in homologous recombination repair genes (BRCA1, BRCA2, ATM, etc.) to identify potential eligibility for targeted therapies 2
• Cross-resistance: Resistance to taxanes is associated with cross-resistance to androgen receptor signaling inhibitors, which may impact treatment sequencing decisions 3
• Continuation of ADT: ADT with an LHRH agonist or antagonist should be continued throughout all treatment phases to maintain castrate serum testosterone levels (<50 ng/dL) 2

Monitoring

• Regular PSA monitoring to assess treatment response 2
• Imaging studies to evaluate for disease progression 2
• Monitoring for treatment-specific adverse effects:
  • 177Lu-PSMA-617: Grade 3 adverse events occurred in 52.7% of patients 2
  • Docetaxel: Monitor for neutropenia, fatigue, and anemia 2
  • Cabazitaxel: Monitor for neutropenia and gastrointestinal effects 2

Clinical Pitfalls to Avoid

• Don't discontinue ADT: Maintaining castrate testosterone levels is essential even when adding other therapies 2
• Don't repeat failed therapy: Patients experiencing disease progression on a given therapy should not repeat that therapy (exception: docetaxel can be given as a rechallenge after progression on a novel hormone therapy if given in the castration-naive setting) 2
• Don't ignore molecular testing: Testing for MSI/MMR and HRR gene mutations is critical for identifying patients who may benefit from targeted therapies 2
• Don't delay treatment sequencing: Prompt initiation of subsequent therapy upon disease progression is important for maintaining disease control 4