What is the most effective treatment for recurrent metastatic castration-resistant prostate cancer?

Most Effective Treatment for Recurrent Metastatic Castration-Resistant Prostate Cancer

For patients with recurrent metastatic castration-resistant prostate cancer (mCRPC), the most effective treatment approach is to use novel hormonal agents such as abiraterone acetate with prednisone, enzalutamide, or apalutamide, depending on prior therapy received. 1

Treatment Algorithm Based on Prior Therapy

First-line mCRPC Treatment:

• For patients who have not received prior novel hormonal therapy:

  • Abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily until disease progression (Category 1 recommendation) 1
  • Enzalutamide 160 mg daily is an alternative first-line option 1
  • Both treatments have demonstrated significant improvement in overall survival and radiographic progression-free survival 1

• For patients with BRCA1/2 alterations:

  • Consider combination therapy with PARP inhibitors plus androgen receptor pathway inhibitors (ARPIs) such as talazoparib + enzalutamide or olaparib + abiraterone 2

Second-line mCRPC Treatment:

• For patients who progressed on abiraterone:

  • Enzalutamide is more effective as second-line therapy than using abiraterone after enzalutamide 3
  • Docetaxel 75 mg/m² every 3 weeks with prednisone is recommended if not previously used 4

• For patients who progressed on enzalutamide:

  • Abiraterone shows limited efficacy after enzalutamide failure 3
  • Consider docetaxel chemotherapy if not previously used 4, 2

Third-line and Beyond:

• For patients who have progressed on both novel hormonal agents and docetaxel:
  • Cabazitaxel chemotherapy 5, 2
  • 177Lu-PSMA-617 (for PSMA-positive tumors) 6, 2
  • For patients with bone-predominant symptomatic disease: Radium-223 1, 2
  • For patients with BRCA1/2 alterations: PARP inhibitor monotherapy (olaparib) 6, 2

Important Considerations

Maintaining Castrate Testosterone Levels:

• Continue androgen deprivation therapy (ADT) indefinitely to maintain castrate levels of testosterone (<50 ng/dL) even during progression 1

Monitoring Requirements:

• For abiraterone: Monitor blood pressure, potassium levels, liver function, and cardiac status due to risk of hypertension, hypokalemia, hepatotoxicity, and cardiac disorders 1, 7
• For enzalutamide: Monitor for fatigue, diarrhea, hot flashes, and seizure risk (reported in 0.9% of patients) 1
• For chemotherapy: Regular monitoring of complete blood counts due to risk of neutropenia 4

Common Pitfalls to Avoid:

• Failing to continue ADT during progression and subsequent therapies 1
• Switching to another androgen receptor-targeted agent without considering the potential for cross-resistance 3
• Not considering the sequence of therapies - evidence shows that abiraterone followed by enzalutamide is more effective than the reverse sequence 3
• Overlooking the need for genetic testing to identify patients who may benefit from PARP inhibitors 6, 2

Evidence Quality and Considerations

• The recommendation for abiraterone and enzalutamide is based on high-quality evidence from randomized controlled trials showing improved overall survival 1
• The optimal sequencing of therapies remains an area of active research, but current evidence favors using abiraterone before enzalutamide when both agents are planned 3
• Novel targeted therapies like PARP inhibitors and 177Lu-PSMA-617 have shown promising results in specific patient populations and should be considered based on molecular profiling 6, 2