How can a patient overcome Zytiga (abiraterone) resistance in metastatic castration-resistant prostate cancer (mCRPC)?

Overcoming Zytiga (Abiraterone) Resistance in mCRPC

When abiraterone fails in metastatic castration-resistant prostate cancer, switch to enzalutamide or cabazitaxel based on prior treatment history and clinical status, or consider docetaxel if chemotherapy-naïve. 1

Treatment Algorithm After Abiraterone Failure

For Patients Who Received Abiraterone BEFORE Docetaxel

Switch to either cabazitaxel or enzalutamide - this is a Standard recommendation from the AUA guidelines for patients with good performance status who have progressed on abiraterone. 1

• Enzalutamide (160 mg daily) is preferred as first-line alternative because it does not require concurrent steroid administration and has lower acute toxicity compared to chemotherapy 2
• Enzalutamide demonstrates strong survival benefit with more favorable side effect profile (fatigue, hypertension, rare seizures) 2
• Cabazitaxel remains effective even after taxane exposure due to low affinity for p-glycoprotein, making it active when other agents fail 1, 3

For Patients Who Received Abiraterone AFTER Docetaxel

Offer enzalutamide or cabazitaxel as standard options for good performance status patients. 1

• Cabazitaxel (with prednisone) showed improved overall survival and progression-free survival in post-docetaxel patients 1
• Primary toxicity is hematological: 82% develop grade 3-4 neutropenia, 8% febrile neutropenia 1
• Prophylactic growth factor support recommended for older patients and those with significant prior radiotherapy 1

For Chemotherapy-Naïve Patients

Docetaxel-based chemotherapy is standard for patients with good performance status, particularly those with symptomatic disease or visceral metastases. 2

• Docetaxel demonstrated landmark survival benefit and remains first-line chemotherapy 1
• Particularly appropriate when disease is rapidly progressive or causing significant symptoms 2

Emerging and Specialized Options

Lutetium-177 PSMA-617 Therapy

Strongly recommended for patients who have failed both docetaxel and androgen pathway inhibitors with PSMA-positive disease confirmed by imaging. 4

• TheraP trial showed superior PSA response rates with Lu-177 PSMA-617 (66%) versus cabazitaxel (37%) in docetaxel-pretreated patients 4, 5
• Grade 3-4 adverse events less frequent (33%) compared to cabazitaxel (53%) 5
• Standard protocol: 4-6 cycles at 6-week intervals 4
• Requires pre-treatment assessment including complete blood count, renal/hepatic function, and performance status 4

Radium-223 for Bone-Predominant Disease

Use specifically for symptomatic bone metastases WITHOUT visceral disease in patients with good performance status. 1, 2

• Improves overall survival while targeting bone metastases 2
• Can be used in patients who have not received prior docetaxel 2

Combination Therapy Approach

Cabazitaxel plus abiraterone combination showed manageable safety profile with 46% PSA response rate in patients previously treated with both docetaxel and abiraterone. 6

• Median PSA-progression-free survival: 6.9 months 6
• Grade 3-4 adverse events: asthenia (14%), neutropenia (14%), diarrhea (8%) 6
• 24% required cabazitaxel dose reductions 6

Critical Monitoring Requirements

Regular monitoring is mandatory regardless of chosen therapy:

• Liver function, potassium levels, and blood pressure with all hormonal therapies 2
• Cardiac monitoring essential in patients with pre-existing cardiovascular disease 2
• PSA response evaluated regularly, but treatment decisions should NOT be based solely on PSA changes 1, 2
• Radiologic imaging (CT, bone scans) to detect progression even when PSA remains undetectable 1

Common Pitfalls to Avoid

Do not use spironolactone with abiraterone - it interferes with abiraterone's mechanism of action and reduces efficacy. 2

Avoid sequential use of abiraterone and enzalutamide without intervening chemotherapy - cross-resistance between these androgen receptor-targeted agents is common. 7

Do not delay treatment changes - early identification of primary or secondary resistance is critical for optimal outcomes. 7

Consider AR-V7 testing before starting additional androgen receptor-targeted therapy - AR-V7 positivity confers resistance to abiraterone/enzalutamide but not to taxane chemotherapies, suggesting early chemotherapy may be more effective. 8

Performance Status Considerations

For poor performance status patients who progressed on abiraterone after docetaxel, palliative care is recommended, though selected patients may receive enzalutamide, ketoconazole plus steroid, or radionuclide therapy. 1

Sequential use of agents is reasonable in patients who remain candidates for further systemic therapy, with clinical trial enrollment and best supportive care as additional options throughout. 1