In a patient with high‑risk locally‑advanced prostate cancer, when should radiotherapy be administered relative to the initiation of abiraterone (100 mg daily) with prednisone?

Timing of Radiotherapy Relative to Abiraterone Initiation in High-Risk Locally Advanced Prostate Cancer

Radiotherapy should be initiated concurrently with abiraterone acetate (1000 mg daily) and prednisone (5 mg daily), with both systemic agents started at the same time as or shortly before the start of radiation therapy. 1

Treatment Regimen and Timing

The evidence-based protocol for high-risk locally advanced prostate cancer requires:

• Abiraterone acetate 1000 mg orally once daily on an empty stomach for 24 months 1
• Prednisone 5 mg orally twice daily (total 10 mg/day) for 24 months 2, 1
• Androgen deprivation therapy (ADT) for a total of 24-36 months (extending beyond abiraterone completion) 1, 3
• External beam radiotherapy delivered concurrently with the above systemic therapy 1, 3

The STAMPEDE trial protocol, which forms the basis for current guidelines, mandated that radiotherapy be delivered as part of the curative-intent treatment plan alongside abiraterone and ADT, not sequentially after completion of systemic therapy. 3

Evidence Supporting Concurrent Administration

The meta-analysis of STAMPEDE trials demonstrated that in patients with high-risk non-metastatic prostate cancer (defined as node-positive disease OR at least 2 of: T3-T4 stage, PSA >40 ng/mL, Gleason 8-10), the combination of abiraterone with ADT and radiotherapy achieved:

• 6-year metastasis-free survival of 82% versus 69% in the control group (HR 0.53,95% CI 0.44-0.64, p<0.0001) 3
• Overall survival benefit with HR 0.60 (95% CI 0.48-0.73, p<0.0001) 3
• Prostate cancer-specific survival with HR 0.49 (95% CI 0.37-0.65, p<0.0001) 3

These outcomes were achieved specifically with concurrent administration of all three modalities. 3

Practical Implementation

Start sequence:

1. Initiate ADT first (can be started 2-4 weeks before other therapies to allow testosterone suppression)
2. Begin abiraterone and prednisone at the time of or shortly before radiotherapy initiation 1, 3
3. Deliver radiotherapy concurrently (typically 74 Gy in 37 fractions to prostate and seminal vesicles, or equivalent hypofractionated schedules) 3

The radiotherapy should be whole-pelvic for node-positive disease and is strongly encouraged even for node-negative patients meeting high-risk criteria. 3

Duration-Specific Considerations

Critical distinction: The 24-month duration of abiraterone is specific to non-metastatic disease receiving curative-intent radiation. 1 In metastatic castration-resistant disease, abiraterone is continued until disease progression, not limited to 24 months. 4 This is a common pitfall—do not extend abiraterone beyond 24 months in the locally advanced non-metastatic setting. 1

Mandatory Monitoring During Concurrent Therapy

Monthly monitoring during the first 3 months is required, then at regular intervals thereafter, including: 2

• Blood pressure – hypertension occurs in ~22% of patients (severe in 4%) 4, 2
• Serum potassium – hypokalemia in ~17% of patients 4, 2
• Serum phosphate – hypophosphatemia in ~24% of patients 4, 2
• Liver enzymes (ALT/AST) – elevations lead to discontinuation in 11-12% of patients 4, 2
• Cardiac assessment – atrial fibrillation in 4%, other cardiac disorders in 19% 4, 2

Common Pitfalls to Avoid

• Do not delay radiotherapy to complete a course of abiraterone first—the survival benefit requires concurrent administration 1, 3
• Do not use abiraterone without radiotherapy in this population—the evidence specifically requires RT as part of the treatment plan 1
• Do not use the 500 mg micronized formulation with methylprednisolone in non-castrate disease, as it lacks FDA approval for this indication 2, 1
• Do not reduce prednisone to once-daily dosing—twice-daily 5 mg dosing is required to prevent mineralocorticoid excess 2

Guideline Consensus

Both ASCO (2021) and ESMO (2023) provide strong recommendations (high-quality evidence) for adding abiraterone to ADT in men with high-risk locally advanced prostate cancer who are receiving radiotherapy, with the understanding that all three modalities are delivered concurrently. 4, 1