What is the role of abiraterone (abiraterone acetate) in the treatment of an older adult male patient with metastatic castrate-sensitive prostate cancer at high risk of progression due to bone metastases?

Abiraterone in Metastatic Castrate-Sensitive Prostate Cancer with High-Risk Bone Metastases

Abiraterone acetate (1000 mg daily) plus prednisone (5 mg twice daily) combined with ADT should be offered to patients with metastatic castrate-sensitive prostate cancer (mCSPC) who have high-risk features, including bone metastases, as this combination significantly improves overall survival compared to ADT alone. 1, 2

Evidence for Abiraterone in High-Risk mCSPC

The recommendation for abiraterone in this setting is based on two landmark phase 3 trials that specifically enrolled patients with newly diagnosed metastatic disease:

LATITUDE Trial (High-Risk Population)

• Enrolled 1,199 men with high-risk mCSPC, defined as having at least 2 of 3 high-risk features: Gleason score 8-10, ≥3 bone metastases, or visceral metastases 1, 2
• Overall survival improved dramatically: median 53.3 months with abiraterone plus prednisone versus 36.5 months with placebo (HR 0.66,95% CI 0.56-0.78; p<0.0001) 3
• Radiographic progression-free survival: 33.0 months versus 14.8 months (HR 0.47,95% CI 0.39-0.55; p<0.001) 2
• Time to pain progression, chemotherapy initiation, and PSA progression all significantly delayed (p<0.001 for all endpoints) 2

STAMPEDE Trial (Broader Population)

• Enrolled 1,917 men with castration-naïve prostate cancer, including those with M1 disease 1
• Demonstrated similar overall survival benefits with abiraterone added to ADT 1
• FDA approval in February 2018 was based on these two trials demonstrating improved OS over ADT alone 1

Current Guideline Recommendations

NCCN Guidelines (2019)

ADT options for M1 castration-naïve disease include 1:

• Orchiectomy plus abiraterone
• LHRH agonist plus abiraterone
• LHRH antagonist plus abiraterone

All combined with prednisone 5 mg once daily 1

ESMO Guidelines (2023)

• ADT plus abiraterone plus prednisone is recommended as first-line treatment for mHSPC (ESMO-MCBS v1.1 score: 4) 1
• Alternative option: triplet therapy with ADT plus docetaxel plus abiraterone plus prednisone for fit men with de novo mHSPC, especially those with multiple bone metastases (>3) or visceral metastases 1
• Both strategies have not been directly compared, but triplet therapy may offer additional benefit in very high-risk patients 1

Treatment Algorithm for High-Risk Bone Metastases

Step 1: Define High-Risk Features

Your patient qualifies for abiraterone if they have at least 2 of the following 1, 2:

• Gleason score 8-10
• ≥3 bone metastases on bone scan
• Visceral metastases

Step 2: Assess Fitness for Treatment Intensification

• Fit patients: Consider triplet therapy (ADT + docetaxel + abiraterone + prednisone), particularly if multiple bone metastases (>3) or visceral disease 1
• Less fit or older patients: ADT + abiraterone + prednisone is appropriate 1
• Vulnerable patients who cannot tolerate intensification: ADT alone should only be used as last resort 1

Step 3: Initiate ADT with Abiraterone

Dosing regimen 1, 2:

• Abiraterone acetate 1000 mg once daily (taken on empty stomach, at least 1 hour before or 2 hours after food)
• Prednisone 5 mg twice daily (or once daily per some protocols)
• Continue ADT indefinitely (orchiectomy, LHRH agonist, or LHRH antagonist)

Step 4: Special Consideration for LHRH Agonist Flare

• In patients with weight-bearing bone metastases at risk for flare symptoms, antiandrogen therapy should precede or be coadministered with LHRH agonist for at least 7 days 1
• LHRH antagonists do not cause flare and do not require antiandrogen coadministration 1

Mandatory Monitoring Requirements

Baseline Assessment

• Blood pressure, serum potassium, liver function tests, cardiac evaluation 4, 5

Ongoing Monitoring

• Monthly monitoring initially, particularly for 5:
  • Liver function tests (hepatotoxicity occurs in 7% grade 3-5)
  • Serum potassium and phosphate (hypokalemia in 12% grade 3-4)
  • Blood pressure (hypertension in 21% grade 3-4)
  • Symptom-directed cardiac assessment

Radiologic and PSA Monitoring

• Monitor with CT, bone scan, and PSA tests for evidence of progression 1
• PSA ≤4 ng/mL after 7 months of ADT is associated with improved survival 1

Adverse Events and Management

Common Mineralocorticoid-Related Effects

The addition of prednisone is mandatory to prevent mineralocorticoid excess from CYP17A1 inhibition 5:

• Hypertension (21% grade 3-4) 3
• Hypokalemia (12% grade 3-4) 3
• Peripheral edema (28% any grade) 5

Other Adverse Events

• Fatigue, hot flushes (hormonal effects) 1
• Hepatotoxicity requiring regular monitoring 1
• Cardiac events (atrial fibrillation rare but slightly increased) 1
• Overall discontinuation rate due to side effects: 12% 1, 3

Age-Related Considerations

• Patients ≥70 years experience increased toxicities (47% vs 33% grade 3-5 adverse events) and may have attenuated survival benefits 4
• Consider this when counseling older patients about treatment intensification 4

Critical Pitfalls to Avoid

Do NOT Combine with Radium-223

• The ERA-223 trial demonstrated that concurrent abiraterone plus radium-223 increased fracture risk (29% vs 11%) without improving symptomatic skeletal event-free survival 6
• This combination is NOT recommended 6

Ensure Proper Fasting Administration

• Abiraterone must be taken on empty stomach due to significantly higher drug exposure with food 1

Do NOT Use Spironolactone for Mineralocorticoid Management

• Spironolactone interferes with abiraterone's mechanism and should be avoided 5
• Eplerenone is an alternative if corticosteroid avoidance is desired, though this remains off-label 5

Continue ADT Indefinitely

• ADT must be continued throughout and after abiraterone treatment 1
• Discontinuing ADT negates the benefit of abiraterone 1

Patient-Reported Outcomes

Quality of life improvements were demonstrated with abiraterone addition 1:

• Improvements in pain intensity progression
• Reduced fatigue
• Better functional status
• Improved prostate cancer-related symptoms
• Enhanced overall health-related QOL

This addresses the priority outcome of quality of life alongside mortality benefits 1.