What is the role of antiandrogens (hormone blockers) in the treatment of a patient with hormone-sensitive prostate cancer?

Antiandrogens in Hormone-Sensitive Prostate Cancer

For patients with hormone-sensitive metastatic or recurrent prostate cancer, bilateral orchiectomy or LHRH agonists are the recommended first-line androgen deprivation therapy (ADT), with nonsteroidal antiandrogen monotherapy as an acceptable alternative in select patients, while combined androgen blockade (CAB) should be considered for those willing to accept increased toxicity for a modest 3-5% survival benefit. 1, 2

Standard First-Line Treatment Options

The foundation of hormonal management consists of two equally effective approaches to achieve castrate testosterone levels (below 50 ng/dL):

• Bilateral orchiectomy (surgical castration) or LHRH agonists (medical castration) represent the standard initial treatments for metastatic hormone-sensitive prostate cancer 1, 3, 4
• Both methods achieve equivalent testosterone suppression and are considered Category 1 evidence 2
• When initiating LHRH agonist therapy, an antiandrogen must be administered for 3-4 weeks initially to prevent testosterone flare 4

Role of Antiandrogen Monotherapy

Nonsteroidal antiandrogen (NSAA) monotherapy merits discussion as an alternative to castration, but steroidal antiandrogen monotherapy should not be offered. 1, 2

Key considerations for NSAA monotherapy:

• Acceptable primarily for patients with locally advanced, non-metastatic disease who wish to preserve sexual function 5
• Provides survival outcomes not significantly different from castration in this specific population 5
• Results in increased testosterone and estradiol levels, leading to gynecomastia and breast pain as common side effects 6, 5
• Critical pitfall: Steroidal antiandrogens (cyproterone acetate) are associated with loss of libido and erectile dysfunction, negating the sexual preservation benefit, and should not be used as monotherapy 1, 5

Combined Androgen Blockade (CAB)

CAB—the addition of a nonsteroidal antiandrogen to medical or surgical castration—should be considered for patients willing to accept increased toxicity for a small survival advantage. 1, 2

Evidence for CAB:

• Provides a 3-5% overall survival advantage compared to castration alone 2
• Particularly beneficial in patients with high-volume metastatic disease, as it blocks residual androgens from adrenal sources that castration alone does not eliminate 2
• The incremental cost is substantial (over $1 million per quality-adjusted life year over orchiectomy alone), which should factor into shared decision-making 1

Specific antiandrogen agents used in CAB:

• Bicalutamide is the most commonly used NSAA due to once-daily dosing and lower gastrointestinal and ophthalmologic adverse effects compared to flutamide and nilutamide 1
• Flutamide is administered at 250 mg three times daily and requires hepatic monitoring due to risk of liver toxicity 2, 7
• All NSAAs in combination with castration achieve "total androgen blockade" 2

Critical Monitoring Requirements

Hepatic monitoring for antiandrogens (especially flutamide):

• Baseline liver function tests before starting treatment 7
• Monthly monitoring for the first 4 months of therapy 7
• Periodic monitoring thereafter 7
• Immediate discontinuation required if: loss of appetite, nausea/vomiting, abdominal pain, fatigue, flu-like symptoms, brown urine, or jaundice occur 7
• Approximately half of liver failure cases occur within the first 3 months of flutamide therapy 7

General ADT monitoring:

• Verify achievement and maintenance of castrate testosterone levels (<50 ng/dL) throughout treatment 2
• PSA measurements every 3-4 weeks initially to assess response 3
• Monitor for ADT-related adverse effects including bone loss, metabolic changes, cardiovascular complications, and sexual dysfunction 2
• Bone density screening is essential for patients on long-term ADT due to increased fracture risk 2

Treatment Duration and Continuity

Continuous ADT is recommended over intermittent ADT for metastatic hormone-naïve prostate cancer. 2, 4

• Current data are insufficient to support routine use of intermittent androgen blockade outside clinical trials 1, 3
• For high-risk localized disease treated with radiation, long-term ADT (2-3 years total duration) is required to achieve survival benefit 2

Timing of ADT Initiation: Early vs. Deferred

The optimal timing remains controversial with nuanced evidence:

• Immediate ADT results in a 17% reduction in relative risk for prostate cancer-specific mortality but a 15% increase in relative risk for non-prostate cancer-specific mortality, with no overall survival advantage 1, 3
• The Panel cannot make a strong recommendation for early ADT initiation given these conflicting mortality outcomes 1
• For patients electing to defer ADT until symptoms, regular monitoring visits are indicated 1
• PSA kinetics and other metrics allow identification of high-risk populations who may benefit from immediate ADT, but further studies are needed 1

Progression to Castration-Resistant Disease

When cancer progresses despite castration (castration-resistant prostate cancer, CRPC):

• Maintain castrate testosterone levels while adding additional therapies 2
• Abiraterone (1000 mg daily) plus low-dose prednisone (5 mg twice daily) is a Category 1 recommendation for asymptomatic/minimally symptomatic metastatic CRPC 2, 8
• Enzalutamide (160 mg daily) blocks androgen receptor activation more potently than first-generation antiandrogens 2, 9
• These newer agents are active in both hormone-sensitive and castration-resistant disease with acceptable tolerability 9

Shared Decision-Making Framework

A full discussion between practitioner and patient must occur to determine optimal therapy, as patients may weigh the balance between favorable and adverse consequences of palliative ADT differently. 1, 4

Key discussion points:

• Sexual function preservation (favors NSAA monotherapy in non-metastatic disease) 5
• Survival benefit magnitude (modest 3-5% with CAB) versus increased toxicity 2
• Cost considerations, particularly for CAB 1
• Quality of life impacts including gynecomastia, hot flashes, fatigue, and metabolic effects 6
• Regular exercise reduces fatigue and improves quality of life in men on ADT 4