What is the role of bicalutamide (Casodex) in treating prostate cancer after developing resistance to Zytiga (abiraterone acetate)?

Bicalutamide After Zytiga (Abiraterone) Resistance

Bicalutamide should not be used after Zytiga resistance develops, as cross-resistance between antiandrogen therapies renders it ineffective, and superior alternatives with proven survival benefits exist.

Why Bicalutamide Fails After Abiraterone

• Cross-resistance is well-established between abiraterone and other antiandrogen therapies through the AKR1C3/AR-V7 axis, meaning cells resistant to abiraterone will also resist bicalutamide 1
• Abiraterone-resistant prostate cancer cells demonstrate cross-resistance to all next-generation antiandrogen drugs, including enzalutamide, apalutamide, and darolutamide, through activation of the steroid hormone biosynthesis pathway and increased AKR1C3 expression 1
• The NCCN explicitly states that switching from one novel hormone therapy (like abiraterone) to another antiandrogen is not the optimal strategy given available alternatives 2

Recommended Treatment Options After Abiraterone Resistance

First-Line Recommendation: Chemotherapy

• Cabazitaxel with prednisone is the preferred option for patients with metastatic CRPC who have progressed on abiraterone and prior docetaxel, demonstrating significantly improved clinical outcomes compared to switching to another antiandrogen 2
• If docetaxel has not yet been used, docetaxel with prednisone should be offered as it provides improved survival and quality of life with a moderate toxicity profile 2

Alternative Options Based on Disease Characteristics

For patients with PSMA-positive disease:

• Lu-177-PSMA-617 demonstrated superior PSA response (66% vs 37%) compared to cabazitaxel with fewer grade 3-4 adverse events (33% vs 53%) in patients previously treated with docetaxel 2

For patients with predominantly bone metastases:

• Radium-223 should be offered as it demonstrates improved survival, improved quality of life, and favorable benefit-harm balance 2

For asymptomatic or minimally symptomatic patients:

• Sipuleucel-T may be considered, showing improved survival in this specific population 2

Why Not Bicalutamide?

• Bicalutamide at 50 mg daily is only indicated for combination therapy with LHRH agonists as initial treatment, not for castration-resistant disease 3, 4
• Even at higher doses (150-200 mg), bicalutamide monotherapy was historically used only for locally advanced disease, not for post-abiraterone resistance 5, 6
• No guideline recommends bicalutamide after progression on abiraterone 2, 7, 8
• The CARD trial definitively showed that chemotherapy (cabazitaxel) significantly outperforms switching to alternative antiandrogen therapy after abiraterone failure 2

Critical Clinical Pitfall

The most common error is attempting to sequence multiple antiandrogen therapies (abiraterone → enzalutamide → bicalutamide) rather than switching to chemotherapy or targeted therapy after first antiandrogen failure. This approach wastes valuable time and exposes patients to ineffective therapy while disease progresses 2, 1.

Treatment Algorithm After Abiraterone Resistance

1. If prior docetaxel exposure: Cabazitaxel + prednisone (Category 1) 2
2. If no prior docetaxel: Docetaxel + prednisone 2
3. If PSMA-positive and prior docetaxel: Consider Lu-177-PSMA-617 2
4. If predominantly bone metastases: Add Radium-223 2
5. If chemotherapy-ineligible and symptomatic: Consider mitoxantrone for palliation only (limited benefit) 2

Continue LHRH agonist/antagonist therapy throughout all subsequent treatments 2, 8.