What type of therapy is abiraterone acetate and how is it used in men with metastatic hormone‑sensitive or castration‑resistant prostate cancer?

Abiraterone Acetate: Hormonal Therapy for Advanced Prostate Cancer

Abiraterone acetate is an oral androgen synthesis inhibitor (hormonal therapy) that blocks CYP17A1 enzyme to prevent testosterone production from adrenal and intratumoral sources, used in combination with prednisone for metastatic castration-resistant and castration-sensitive prostate cancer. 1, 2

Mechanism of Action

Abiraterone acetate functions as a selective, irreversible inhibitor of cytochrome P450 17α-hydroxylase (CYP17A1), a key enzyme that metabolizes testosterone and dihydrotestosterone from weak adrenal androgens. 1, 3 This mechanism addresses the critical finding that prostate cancer continues to be driven by androgen signaling even after castration, through autocrine and paracrine androgen synthesis in the tumor microenvironment. 1, 4

Clinical Indications and Evidence

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Post-Docetaxel Setting (Category 1 - Strongest Evidence):

• Abiraterone 1,000 mg daily plus prednisone 5 mg twice daily significantly improves overall survival from 10.9 to 14.8 months (HR 0.65; 95% CI 0.54-0.77; P<0.001) in men who have progressed after docetaxel chemotherapy. 1
• This represents the pivotal approval data and is considered standard of care. 1, 5
• Additional benefits include improved time to radiographic progression, PSA decline, and pain palliation. 1

Pre-Chemotherapy Setting (Category 1):

• In asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients, abiraterone improves median radiographic progression-free survival from 8.3 to 16.5 months (HR 0.53; 95% CI 0.45-0.62; P<0.001). 6, 3
• Overall survival shows improvement with median not reached versus 27.2 months (HR 0.75; 95% CI 0.61-0.93). 6
• Delays pain progression (26.7 vs 18.4 months; HR 0.82; P=0.049) and functional decline (12.7 vs 8.3 months; HR 0.78; P=0.003). 6

Metastatic Castration-Sensitive Prostate Cancer (Category 1)

First-Line Treatment with ADT:

• In newly diagnosed metastatic castration-sensitive prostate cancer with high-risk features (≥2 of: Gleason 8-10, ≥3 bone metastases, visceral metastases), abiraterone plus prednisone with ADT significantly improves overall survival from 34.7 months to not reached (HR 0.62; 95% CI 0.51-0.76; P<0.001). 1, 7
• At 30 months follow-up, estimated 3-year overall survival improved from 49% to 66%. 1
• Delays castration-resistant radiographic progression from median 14.8 to 33.2 months and PSA progression from 7.4 to 33.2 months. 1, 2
• Patient-reported outcomes show improvements in pain intensity, fatigue, functional decline, and overall quality of life. 1

Dosing and Administration

Standard Dosing:

• Abiraterone acetate 1,000 mg orally once daily (four 250-mg tablets) plus prednisone 5 mg orally twice daily. 1, 8
• Critical requirement: Must be taken on an empty stomach (at least 1 hour before or 2 hours after meals) due to significantly increased drug exposure with food. 6, 8
• Do not crush or chew tablets. 8

Alternative Low-Dose Regimen (Category 2B):

• Abiraterone 250 mg once daily with a low-fat breakfast may reduce financial toxicity and improve compliance, though this is a lower evidence recommendation. 2, 5

Concurrent Therapy:

• Patients must continue ADT (GnRH agonist/antagonist) concurrently or have had bilateral orchiectomy to maintain castrate testosterone levels <50 ng/dL. 5, 8
• Prednisone 5 mg twice daily is mandatory to prevent mineralocorticoid excess from increased ACTH levels. 1

Mandatory Monitoring Requirements

Baseline Assessment:

• Blood pressure measurement 6, 5
• Serum potassium levels 6, 5
• Liver function tests (AST, ALT, bilirubin) 6, 5
• Cardiac evaluation 6, 5

Ongoing Monitoring (At Least Monthly):

• Blood pressure and symptoms of fluid retention 1, 6
• Serum potassium with correction of hypokalemia before initiating therapy 1, 6
• Liver function tests (monthly initially, then as clinically indicated) 6, 5
• Radiologic imaging (CT, bone scan), PSA tests, and clinical examinations for disease progression 1
• Blood glucose monitoring in diabetic patients, particularly those on thiazolidinediones or repaglinide 8

Adverse Events and Management

Mineralocorticoid-Related Effects (Most Common):

• Hypertension (21% grade 3-4) 6, 3
• Hypokalemia (28% any grade, 12% grade 3-4) 1, 6
• Peripheral edema (28% any grade) 6, 3
• Critical pitfall: Do NOT use spironolactone for mineralocorticoid management as it interferes with abiraterone's mechanism. 6

Hepatotoxicity:

• Grade 3-5 liver toxicity occurs in approximately 7% of patients. 6, 5
• Most common cause of drug discontinuation (<1%) includes elevated AST/ALT. 1
• Hold therapy until recovery if hepatotoxicity develops; may retreat at reduced dose. 8

Cardiac Events:

• Severe hypertension or cardiac disorders in approximately 10% of patients. 6, 5
• Atrial fibrillation rare but slightly increased. 1

Other Common Side Effects (>5%):

• Joint swelling/discomfort, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, urinary frequency, nocturia, dyspepsia, upper respiratory infection. 1, 3
• Most events are grade 1-2 and generally well tolerated. 1
• Overall discontinuation rate due to adverse events approximately 12%. 1, 5

Age-Related Considerations

Critical caveat for elderly patients:

• Survival benefit is significantly larger in men <70 years (HR 0.51) compared to older men (HR 0.94). 6, 5
• Older men experience substantially higher rates of grade 3-5 adverse events (47% vs 33%) and treatment-related deaths. 6, 5
• Exercise increased caution and closer monitoring in elderly patients, particularly those with cardiovascular comorbidities. 6

Dose Modifications

Hepatic Impairment:

• For baseline moderate hepatic impairment (Child-Pugh Class B), reduce starting dose to 250 mg once daily. 8

Strong CYP3A4 Inducers:

• Avoid concomitant use during treatment. 8
• If unavoidable, increase abiraterone dosing frequency. 8

CYP2D6 Substrates:

• Avoid co-administration with CYP2D6 substrates with narrow therapeutic index. 8
• If unavoidable, consider dose reduction of the CYP2D6 substrate. 8

Critical Contraindications

Absolute contraindication:

• Do NOT combine abiraterone with radium-223, as this increases fracture risk without improving symptomatic skeletal event-free survival. 6

Treatment Selection Algorithm

For Newly Diagnosed Metastatic Castration-Sensitive Prostate Cancer:

• Offer ADT + abiraterone + prednisone if high-risk features present (≥2 of: Gleason 8-10, ≥3 bone metastases, visceral metastases). 1, 6

For Metastatic Castration-Resistant Prostate Cancer:

• Asymptomatic/mildly symptomatic, chemotherapy-naïve: Abiraterone or enzalutamide as first-line (Category 1). 6, 5
• Symptomatic with good performance status: Abiraterone, enzalutamide, or docetaxel. 6
• Post-docetaxel progression: Abiraterone is standard of care (Category 1). 1, 5
• Symptomatic but not candidates for docetaxel: Abiraterone with prednisone is appropriate given survival and palliative benefit with reasonable toxicity (Category 2B). 1