What is the recommended treatment for a male patient over 50 with metastatic castration-resistant prostate cancer, specifically considering Abiraterone (abiraterone acetate) as a first-line option?

Abiraterone for Metastatic Castration-Resistant Prostate Cancer

Abiraterone acetate 1,000 mg orally once daily plus prednisone 5 mg orally twice daily is a Category 1 first-line treatment option for metastatic castration-resistant prostate cancer (mCRPC), particularly for asymptomatic or mildly symptomatic patients who have not received prior chemotherapy. 1, 2

First-Line Treatment Recommendation

For chemotherapy-naïve mCRPC patients, abiraterone represents a standard of care alongside enzalutamide, with high-level evidence supporting its use. 1 The NCCN designates this as a Category 1 recommendation, indicating uniform consensus based on the strongest evidence. 1

Evidence Base for First-Line Use

• The COU-AA-302 trial demonstrated that abiraterone improved median overall survival from 30.3 to 34.7 months (HR 0.81, P=0.003) in chemotherapy-naïve patients. 3
• Radiographic progression-free survival improved significantly from 8.2 to 16.5 months (HR 0.52, P<0.0001). 4
• All clinically relevant secondary endpoints improved, including time to pain progression, PSA progression, and initiation of chemotherapy. 1, 4

Dosing and Administration Protocol

Standard dosing: Abiraterone acetate 1,000 mg (four 250 mg tablets or two 500 mg tablets) orally once daily plus prednisone 5 mg orally twice daily. 2

Critical Administration Requirements

• Must be taken on an empty stomach (at least 1 hour before or 2 hours after a meal) to avoid unpredictable drug levels. 2
• Tablets must be swallowed whole with water—do not crush or chew. 2
• Patients must continue concurrent GnRH analog therapy or have had bilateral orchiectomy to maintain castrate testosterone levels below 50 ng/dL. 1, 2

Alternative Dosing Option

• Category 2B alternative: 250 mg once daily with a low-fat breakfast plus prednisone 5 mg twice daily may reduce financial toxicity and improve compliance, though this is a lower-level recommendation. 1, 3

Mandatory Monitoring Requirements

Baseline Assessment

• Blood pressure measurement 1
• Serum potassium and phosphate levels 3
• Liver function tests (ALT, AST, bilirubin) 1, 2
• Cardiac evaluation 1

Ongoing Monitoring

• Monthly monitoring of blood pressure, serum potassium, and symptoms of fluid retention. 1, 2
• Regular liver function monitoring, especially during the first 3 months. 2
• For elderly patients (≥75 years), monthly monitoring of blood pressure, serum potassium, phosphate, and liver function tests is particularly important. 3

Expected Adverse Events and Management

Common Adverse Events (≥10%)

• Mineralocorticoid excess effects: hypertension, hypokalemia, edema, and fluid retention 1, 2
• Musculoskeletal: arthralgia, joint swelling, muscle discomfort 1
• Constitutional: fatigue, hot flush 2
• Gastrointestinal: diarrhea, nausea, vomiting 2
• Other: urinary tract infection, cough, upper respiratory infection, headache 2

Serious Adverse Events

• Severe hypertension or cardiac disorders occur in approximately 10% of patients. 1
• Grade 3-5 liver toxicity occurs in approximately 7% of patients. 1
• Overall discontinuation rate due to adverse events is approximately 12%. 1

Hepatotoxicity Management Algorithm

If ALT/AST >5× ULN or total bilirubin >3× ULN:

• Interrupt abiraterone treatment immediately. 2
• May restart at 750 mg once daily after liver function returns to baseline or AST/ALT ≤2.5× ULN and bilirubin ≤1.5× ULN. 2
• If hepatotoxicity recurs at 750 mg, may restart at 500 mg once daily after recovery. 2
• Discontinue permanently if hepatotoxicity recurs at 500 mg dose. 2

Special Considerations for Elderly Patients

The survival benefit of abiraterone is significantly larger in men under 70 years of age (HR 0.51) compared to older men (HR 0.94). 1, 3

Age-Related Toxicity Concerns

• Elderly patients (≥75 years) experience higher rates of grade 3-5 adverse events (47% vs 33%). 1, 3
• Treatment-related deaths are higher in older men (9 vs 3). 1, 3
• Despite these concerns, abiraterone remains an appropriate option for fit elderly patients with careful monitoring. 1

Critical Drug Interactions

• Avoid concomitant strong CYP3A4 inducers during abiraterone treatment; if unavoidable, increase dosing frequency. 2
• Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index; if unavoidable, consider dose reduction of the CYP2D6 substrate. 2

Hepatic Impairment Dosing

• Moderate hepatic impairment (Child-Pugh Class B): Reduce starting dose to 250 mg once daily with enhanced monitoring (weekly for first month, every 2 weeks for next 2 months, then monthly). 2
• Severe hepatic impairment (Child-Pugh Class C): Do not use abiraterone. 2

Post-Chemotherapy Setting

For patients who have received prior docetaxel, abiraterone plus prednisone significantly improved overall survival from 10.9 to 14.8 months (HR 0.74, P<0.0001), representing the strongest FDA-approved indication for post-chemotherapy CRPC. 1, 3

Important Contraindications and Warnings

• Do not combine with radium Ra 223 dichloride: Increased fractures and mortality have been observed with this combination. 2
• Hypoglycemia risk: Severe hypoglycemia reported in diabetic patients taking thiazolidinediones or repaglinide; monitor blood glucose and adjust antidiabetic medications as needed. 2
• Embryo-fetal toxicity: Males with female partners of reproductive potential must use effective contraception. 2