What is the role of Abiraterone (abiraterone) in treating castration-resistant prostate cancer?

Role of Abiraterone in Treating Castration-Resistant Prostate Cancer

Abiraterone acetate plus prednisone is a standard first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), demonstrating significant improvements in overall survival and radiographic progression-free survival. 1

Mechanism of Action

• Abiraterone is an irreversible inhibitor of CYP17A, blocking androgen biosynthesis in adrenal glands and tumor tissue
• Must be administered with prednisone (5 mg twice daily) to prevent mineralocorticoid excess caused by CYP17 inhibition 2

Clinical Indications

FDA-Approved Indications

• Treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone 3
• Also approved for metastatic castration-sensitive prostate cancer (not the focus of this question)

Patient Selection for mCRPC

1. Asymptomatic/Minimally Symptomatic mCRPC (First-Line)

   • Standard therapy for patients with good performance status who have not received docetaxel 1
   • Evidence Level Grade A recommendation 1

2. Symptomatic mCRPC

   • Option for patients with symptomatic mCRPC, even with poor performance status 1
   • Evidence Level Grade C recommendation 1

3. Post-Docetaxel mCRPC

   • Significant survival benefit demonstrated in patients who progressed after docetaxel 4

Efficacy in mCRPC

Pre-Chemotherapy Setting

• Radiographic progression-free survival: 16.5 months with abiraterone vs. 8.3 months with prednisone alone (HR 0.53) 5
• Trend toward improved overall survival (median not reached vs. 27.2 months; HR 0.75) 5
• Significantly delayed time to:
  • Initiation of cytotoxic chemotherapy
  • Opiate use for cancer-related pain
  • PSA progression
  • Performance status decline

Post-Chemotherapy Setting

• Overall survival: 14.8 months vs. 10.9 months with placebo (HR 0.65) 4
• Time to PSA progression: 10.2 vs. 6.6 months (p<0.001) 4
• Progression-free survival: 5.6 vs. 3.6 months (p<0.001) 4
• PSA response rate: 29% vs. 6% (p<0.001) 4

Administration

• Standard dose: 1,000 mg orally once daily with prednisone 5 mg orally twice daily 3
• Must be taken on an empty stomach with water (at least 1 hour before or 2 hours after a meal) 3
• Alternative lower-cost option: 250 mg daily with a low-fat breakfast 2
• Fine-particle formulation (500 mg) is bioequivalent to 1,000 mg of original formulation 1, 2
• Continue GnRH analog therapy concurrently unless patient has had bilateral orchiectomy 3

Monitoring and Side Effect Management

Required Monitoring

• Blood pressure: monthly 2
• Serum potassium: monthly 2
• Liver function tests: monthly, at least initially 2
• Phosphate levels: monthly 2
• Signs of fluid retention: monthly 2
• Cardiac symptoms: as needed 2

Common Side Effects

• Mineralocorticoid-related: hypertension (22%), hypokalemia (17-28%), peripheral edema (28%) 2, 5
• Cardiovascular: atrial fibrillation (4%), potential congestive heart failure 2
• Hepatotoxicity: elevated liver enzymes (11-12%) 2
• Other: fatigue (39%), arthralgia/back pain (28-32%), hot flushes (22%) 2

Special Considerations

1. Dose Modifications

   • For moderate hepatic impairment (Child-Pugh Class B): reduce starting dose to 250 mg once daily 3
   • For hepatotoxicity during treatment: hold until recovery, then restart at reduced dose 3
   • Discontinue for severe hepatotoxicity 3

2. Drug Interactions

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

3. Contraindications

   • No absolute contraindications listed in FDA label 3
   • Use with caution in patients with pre-existing cardiovascular disease 2

Sequencing in Treatment Algorithm

For patients with mCRPC, the treatment algorithm should follow:

1. First-Line Options (choose one):

   • Abiraterone + prednisone (especially for asymptomatic/minimally symptomatic)
   • Docetaxel + prednisone (especially for symptomatic disease)
   • Sipuleucel-T (for asymptomatic/minimally symptomatic with good performance status)

2. Upon Progression:

   • If abiraterone used first-line → consider docetaxel
   • If docetaxel used first-line → consider abiraterone

Pitfalls to Avoid

1. Failure to co-administer prednisone - Essential to prevent mineralocorticoid excess 2
2. Inadequate monitoring - Regular assessment of blood pressure, electrolytes, and liver function is crucial 2
3. Food effects - Taking with food significantly impacts absorption, leading to unpredictable effects 2
4. Dose escalation at resistance - Increasing dose to 1000 mg twice daily at progression shows no benefit 6
5. Combination with radium Ra 223 dichloride - Not recommended due to increased fractures and mortality 3

Abiraterone has transformed the treatment landscape for mCRPC, offering significant survival benefits with manageable toxicity when properly monitored and administered.