Why is Abiraterone (abiraterone) used in the treatment of metastatic castration-resistant prostate cancer (mCRPC)?

Abiraterone in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Abiraterone acetate is used in metastatic castration-resistant prostate cancer because it significantly improves overall survival by inhibiting androgen synthesis, which slows disease progression and delays clinical deterioration even after conventional androgen deprivation therapy has failed.

Mechanism of Action

Abiraterone works by targeting the androgen signaling pathway that remains active in mCRPC:

• Functions as an irreversible inhibitor of CYP17A enzyme (both hydroxylase and lyase activities) 1
• Blocks androgen synthesis from non-gonadal sources (adrenal glands and tumor microenvironment) 1
• Prevents autocrine and paracrine androgen production that drives tumor growth despite castrate testosterone levels 1

Clinical Evidence Supporting Use

Post-Docetaxel Setting

• FDA approval in April 2011 based on COU-AA-301 trial 1
• Demonstrated improved median survival (15.8 vs 11.2 months; HR 0.74) compared to placebo 1
• Also improved time to radiographic progression, PSA decline, and pain palliation 1

Pre-Docetaxel Setting

• FDA approval in December 2012 based on COU-AA-302 trial 1
• Significantly improved radiographic progression-free survival (16.5 vs 8.3 months; HR 0.53) 2
• Improved overall survival (34.7 vs 30.3 months; HR 0.81) 1
• Delayed clinical decline with improvements in:
  • Time to chemotherapy initiation
  • Time to opiate use for cancer pain
  • Time to PSA progression
  • Time to performance status decline 1, 2

Treatment Algorithm

1. Patient Selection:

   • Indicated for patients with mCRPC regardless of symptom burden 1
   • Can be used before chemotherapy (first-line) or after docetaxel failure 1
   • Standard therapy for asymptomatic/minimally symptomatic patients with good performance status 1

2. Administration:

   • Standard dose: 1,000 mg orally once daily 3
   • Must be given with prednisone 5 mg twice daily to prevent mineralocorticoid excess 3
   • Alternative options:
     • Fine-particle formulation: 500 mg (bioequivalent to 1,000 mg of original) 1
     • Low-cost option: 250 mg with low-fat breakfast 1
   • Take on empty stomach (1 hour before or 2 hours after meals) 3
   • Continue GnRH analog therapy to maintain castrate testosterone levels 3

3. Monitoring During Treatment:

   • Monthly assessment of blood pressure, potassium levels, and liver function 4
   • Regular monitoring for fluid retention and cardiac symptoms 4
   • Continue until clinical progression or intolerable side effects 1
   • Even with undetectable PSA, bone imaging may reveal progression 1

Common Adverse Effects

• Fatigue (39% of patients) 1
• Musculoskeletal discomfort (28-32%) 1
• Peripheral edema (28%) 1, 4
• Hypertension (22%, severe in 4%) 1, 4
• Gastrointestinal effects (diarrhea, nausea, constipation) (22%) 1
• Hypokalemia (17%) and hypophosphatemia (24%) 1, 4
• Hot flushes (22%) 1
• Liver function abnormalities (11-12%, can lead to discontinuation) 1, 4
• Atrial fibrillation (4%) 1, 4

Clinical Pitfalls and Caveats

1. Mineralocorticoid Effects:

   • Always administer with prednisone to prevent mineralocorticoid excess 3
   • Monitor for hypertension, hypokalemia, and fluid retention 4

2. Hepatotoxicity:

   • Monitor liver function tests monthly 4
   • Dose reduction or interruption may be needed for hepatotoxicity 3
   • For moderate hepatic impairment, start at reduced dose (250 mg daily) 3

3. Drug Interactions:

   • Avoid strong CYP3A4 inducers during treatment 3
   • Use caution with CYP2D6 substrates that have narrow therapeutic index 3

4. Treatment Sequencing:

   • Limited data to inform optimal sequence of agents in mCRPC 1
   • Sequential use is reasonable in patients who remain candidates for further therapy 1
   • If abiraterone was used before docetaxel, consider cabazitaxel or enzalutamide after docetaxel 1

5. Continued ADT:

   • Maintain castrate testosterone levels by continuing androgen deprivation therapy 1, 3
   • Do not discontinue LHRH agonist/antagonist during abiraterone treatment 3

Abiraterone has transformed the treatment landscape for mCRPC by providing a well-tolerated option that effectively targets persistent androgen signaling, improving survival and quality of life in this challenging disease setting.