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

FDA-Approved Indication and Dosing

• Abiraterone acetate is FDA-approved in combination with prednisone for metastatic CRPC 2
• The standard regimen is abiraterone 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily plus prednisone 5 mg orally twice daily 2
• Abiraterone must be taken on an empty stomach, at least one hour before or at least two hours after a meal 2
• Tablets should be swallowed whole with water and not crushed or chewed 2
• Patients must continue concurrent GnRH analog therapy or have had bilateral orchiectomy to maintain castrate testosterone levels 2

Evidence for First-Line Use in mCRPC

For asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients, abiraterone is a recommended first-line option based on high-quality evidence:

• The COU-AA-302 trial demonstrated significant improvement in radiographic progression-free survival (16.5 vs 8.2 months; HR 0.52, P<0.0001) and overall survival (35.3 vs 30.1 months; HR 0.79, P=0.0151) in chemotherapy-naïve mCRPC patients 3
• ESMO guidelines recommend abiraterone or enzalutamide as first-line options for asymptomatic/mildly symptomatic chemotherapy-naïve mCRPC (Level I, A evidence) 1
• NCCN designates this as a Category 1 recommendation, indicating high-level evidence and uniform consensus 1, 4

Alternative Dosing to Reduce Financial Toxicity

• An alternative dosing of 250 mg once daily with a low-fat breakfast plus prednisone 5 mg twice daily is a Category 2B option that may reduce financial toxicity and improve compliance 1, 5
• This lower-dose regimen with food has not been as extensively studied but offers potential cost savings 1

Mandatory Monitoring Requirements

Before initiating treatment:

• Assess baseline blood pressure, serum potassium, liver function tests (ALT, AST, bilirubin), and cardiac function 4, 2

During treatment:

• Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly 4, 2
• Monitor liver function tests regularly, particularly in the first three months 2
• For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce starting dose to 250 mg once daily and monitor ALT, AST, and bilirubin weekly for the first month, every two weeks for the next two months, then monthly 2

Critical Safety Considerations

Mineralocorticoid excess effects:

• Hypertension, hypokalemia, and fluid retention/edema are common due to CYP17 inhibition 4, 2
• Control hypertension and correct hypokalemia before starting treatment 2
• Severe hypertension or cardiac disorders occur in approximately 10% of patients 1

Hepatotoxicity:

• Grade 3-5 liver toxicity occurs in approximately 7% of patients 1
• If ALT/AST >5× ULN or total bilirubin >3× ULN develops, interrupt treatment 2
• May restart at reduced dose (750 mg daily, then 500 mg daily if recurs) after liver function normalizes 2
• Discontinue permanently if severe hepatotoxicity recurs at 500 mg daily 2

Age-related considerations:

• The survival benefit is larger in men <70 years (HR 0.51) compared to older men (HR 0.94) 1, 4
• Older men experience significantly higher rates of grade 3-5 adverse events (47% vs 33%) and treatment-related deaths (9 vs 3) 1, 4, 5
• More intensive monitoring is warranted in elderly patients 5

Common Adverse Events

The most frequently reported adverse reactions (≥10%) include fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache 2

Contraindication for Combination Therapy

Do not use abiraterone plus prednisone in combination with radium-223 dichloride, as this increases fractures and mortality 2

Place in Treatment Algorithm

For chemotherapy-naïve mCRPC:

• Abiraterone is a first-line standard of care alongside enzalutamide 1
• The choice between abiraterone and enzalutamide should be based on patient comorbidities, side effect profiles, and patient preference 1

For post-docetaxel mCRPC:

• Abiraterone remains a recommended option with proven survival benefit (median OS 14.8 vs 10.9 months) 4, 6
• Other options include enzalutamide, cabazitaxel, and radium-223 (for bone-predominant disease without visceral metastases) 1

Key Clinical Pitfalls to Avoid

• Do not administer with food unless using the intentional low-dose regimen, as food significantly increases absorption unpredictably 5, 2
• Do not discontinue GnRH analog therapy even after starting abiraterone; castrate testosterone levels must be maintained 2
• Do not use in patients with baseline severe hepatic impairment (Child-Pugh Class C) 2
• Do not overlook cardiovascular monitoring, especially in patients with pre-existing cardiovascular disease, as cardiac events are a significant concern 1, 2