What is the role of nonsteroidal antiandrogens (NSAAs), such as bicalutamide (Casodex), in the treatment of a patient with advanced or metastatic prostate cancer?

Nonsteroidal Antiandrogens in Advanced/Metastatic Prostate Cancer

In resource-constrained settings where newer agents like abiraterone are unavailable, combined androgen blockade using ADT plus a first-generation nonsteroidal antiandrogen (bicalutamide, flutamide, or nilutamide) may be offered for locally advanced nonmetastatic prostate cancer rather than castration monotherapy, but these agents are NOT preferred first-line therapy when newer options are accessible. 1

Current Role: Second-Tier Option in Modern Treatment Paradigm

Preferred First-Line Approaches for Metastatic Disease

For patients with metastatic noncastrate prostate cancer, the standard of care has evolved beyond first-generation antiandrogens:

• ADT plus abiraterone and prednisone is the preferred regimen, demonstrating significant failure-free survival benefits (HR: 0.21,95% CI 0.15-0.31, P<0.05) 1
• ADT plus enzalutamide (160 mg daily) provides significant benefits in PSA progression-free survival, clinical progression-free survival, and overall survival compared to first-generation antiandrogens plus ADT 1
• ADT plus apalutamide (240 mg daily) is strongly recommended, with significantly longer radiographic progression-free survival and overall survival at 22.7 months compared to ADT plus placebo 1

When NSAAs Remain Relevant

Combined androgen blockade with NSAAs is relegated to resource-constrained settings where second-generation agents are unavailable or unaffordable 1:

• Meta-analysis of 16 RCTs (6,084 patients) showed combined androgen blockade with NSAAs improved overall survival (HR: 0.88,95% CI 0.82-0.95, P=0.0009) and progression-free survival (HR: 0.85,95% CI 0.73-0.98, P=0.007) compared to castration monotherapy 1
• This represents a moderate strength recommendation with high-quality evidence, but only when better options are inaccessible 1

Specific NSAA Agents and Dosing

Bicalutamide (Casodex)

For combined androgen blockade: 50 mg once daily with LHRH agonist 1, 2:

• Demonstrated equivalent efficacy to flutamide 250 mg three times daily when combined with LHRH agonist, with longer median survival (though not statistically significant overall) 1
• Better tolerated than flutamide: only 2 patients withdrew due to diarrhea versus 25 with flutamide 1
• Highly protein-bound (96%) with half-life of 5.8 days, allowing once-daily dosing 2

For monotherapy in locally advanced nonmetastatic disease: 150 mg once daily 1, 3:

• Provides equivalent survival to castration in M0 locally advanced disease (median survival 63.5 vs 69.9 months, not statistically different) 3, 4
• Significantly better preservation of sexual interest (p=0.029) and physical capacity (p=0.046) compared to castration 3
• Critical caveat: Monotherapy with 50 mg is insufficient and less effective than castration 1, 5

Nilutamide

Dosing: Standard regimen post-orchiectomy 1:

• Meta-analysis of 5 RCTs (1,842 patients) showed nilutamide post-orchiectomy improved disease control rate (RR: 1.21,95% CI 1.12-1.31, P<0.0001) and objective response (RR: 1.68,95% CI 1.42-1.99, P<0.0001) 1
• Associated with ophthalmologic adverse effects (difficulty with light/dark adaptation) and interstitial pneumonitis not seen with bicalutamide 5

Flutamide

Dosing: 250 mg three times daily 1:

• Requires three-times-daily dosing due to 5-6 hour half-life of active metabolite 1
• Higher incidence of diarrhea (9.8% withdrawal rate) and gastrointestinal adverse effects compared to bicalutamide 1

Monitoring and Safety Considerations

Hepatotoxicity Surveillance

All NSAAs require periodic liver function monitoring 1, 2:

• Diarrhea and liver dysfunction/elevated liver enzymes are statistically significantly more likely with combined androgen blockade 1
• Use with caution in moderate-to-severe hepatic impairment; half-life of bicalutamide R-enantiomer increases 76% in severe liver disease 2
• Changes in hepatic function are generally transient and resolve during or after therapy withdrawal 5

Common Adverse Effects

Pharmacological side effects differ from castration 3, 4:

• With NSAAs: Breast pain and gynecomastia (up to 39% of patients) 1, 3
• With castration: Hot flashes predominate 3
• Grade 3/4 adverse events are otherwise similar between combined androgen blockade and monotherapy 1

Critical Pitfall to Avoid

Never discontinue ADT when disease progresses on NSAA therapy 1:

• Continue ADT indefinitely to maintain castrate testosterone levels (<50 ng/dL) even during progression 1
• When switching to second-generation agents or chemotherapy, maintain concurrent ADT 6, 7

Evidence Quality and Strength

The 2021 ASCO guidelines provide the most authoritative framework 1:

• High-quality evidence supports NSAAs in combined androgen blockade, but with moderate strength recommendation 1
• This contrasts with strong recommendations for abiraterone, enzalutamide, and apalutamide combinations 1
• The evidence base for NSAAs dates primarily from 1990-2014 trials, predating the second-generation agent era 1

Clinical Decision Algorithm

Step 1: Assess resource availability and patient fitness:

• If abiraterone, enzalutamide, or apalutamide are accessible → proceed with these agents plus ADT 1
• If only first-generation agents available → proceed to Step 2

Step 2: For locally advanced nonmetastatic disease:

• Bicalutamide 150 mg daily monotherapy is acceptable alternative to castration 1, 3, 4
• Emphasize quality of life benefits (sexual function preservation) 3, 4

Step 3: For metastatic disease requiring combined androgen blockade:

• Bicalutamide 50 mg daily plus LHRH agonist is preferred NSAA option (once-daily dosing, better tolerability) 1
• Alternative: Flutamide 250 mg three times daily or nilutamide (if patient can tolerate more frequent dosing and GI effects) 1

Step 4: Establish monitoring protocol:

• Baseline and periodic liver function tests 1, 2
• PSA every 3-6 months 6
• Maintain ADT indefinitely regardless of progression 1, 6