What is the recommended treatment for advanced prostate cancer using androgen deprivation therapy (ADT)?

Androgen Deprivation Therapy for Advanced Prostate Cancer

Primary Recommendation

For metastatic hormone-sensitive prostate cancer, bilateral orchiectomy or LHRH agonists (such as leuprolide or goserelin) represent the standard first-line androgen deprivation therapy, with LHRH agonists requiring concurrent antiandrogen coverage for 3-4 weeks to prevent testosterone flare. 1, 2

Standard Treatment Options

Surgical vs Medical Castration

• Bilateral orchiectomy provides permanent testosterone suppression and is the most cost-effective option when available, avoiding ongoing medication costs and compliance issues 1

• LHRH agonists (leuprolide, goserelin, triptorelin, buserelin) are the most commonly prescribed medical castration agents and achieve equivalent survival outcomes to surgical castration 1, 2, 3

• LHRH antagonists (degarelix) offer the advantage of immediate testosterone suppression without initial surge, eliminating the need for antiandrogen coverage and may be preferred in patients with high tumor burden or spinal cord compression 4, 5

Critical Implementation Detail

• When initiating LHRH agonist therapy, you must prescribe a nonsteroidal antiandrogen (flutamide, bicalutamide, or nilutamide) for 3-4 weeks to prevent testosterone flare and potential clinical deterioration 2

• This antiandrogen coverage is not required with LHRH antagonists due to their immediate suppressive effect 5

Enhanced Treatment Strategies

Combined Androgen Blockade

• Combined androgen blockade (CAB) using LHRH agonist plus nonsteroidal antiandrogen provides a small but statistically significant survival benefit (approximately 2-3% absolute improvement at 5 years) compared to castration alone 1, 2

• The survival benefit must be weighed against increased toxicity, including gynecomastia (up to 39%), breast pain, and hepatotoxicity 1

• Offer CAB to patients willing to accept increased side effects for modest survival gain, particularly those with high-volume metastatic disease 1, 2

Intensified Therapy for Locally Advanced Disease

• For noncastrate locally advanced nonmetastatic prostate cancer, ADT plus abiraterone and prednisone should be strongly considered over castration monotherapy, based on significant failure-free survival benefit from the STAMPEDE trial 1

• This combination is administered for 2 years or less in the nonmetastatic setting 1

• In resource-constrained settings where abiraterone is unavailable, combined androgen blockade using ADT plus first-generation antiandrogen (flutamide, nilutamide, or bicalutamide) represents an acceptable alternative 1

Timing Considerations

Early vs Deferred ADT

• Early (immediate) ADT may be offered to men with locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiation therapy 1

• Early ADT provides modest but statistically significant benefits in overall survival and cancer-specific survival compared to deferred therapy 1

• Deferred ADT remains appropriate for asymptomatic patients who wish to avoid or delay ADT-related side effects, though this risks loss of hormone sensitivity and serious complications such as spinal cord compression 1

• For patients with PSA relapse after local treatment, insufficient evidence exists to make a firm recommendation regarding timing 1

Continuous vs Intermittent ADT

• Continuous ADT is recommended over intermittent ADT for metastatic hormone-naïve prostate cancer 2

• Intermittent therapy may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer after radical prostatectomy and/or radiation therapy, as meta-analyses demonstrate noninferiority for overall survival 1

Antiandrogen Monotherapy

When NOT to Use

• Nonsteroidal antiandrogens as monotherapy may be discussed as an alternative to castration in select patients who prioritize sexual function and physical capacity, though they provide inferior overall survival compared to castration (hazard ratio 1.22,95% CI 0.99-1.50) 1

• Steroidal antiandrogens (cyproterone acetate) should NOT be offered as monotherapy due to inferior efficacy compared to LHRH agonists and risk of hepatotoxicity 1

Comparative Efficacy of LHRH Agonists

• All LHRH agonists (goserelin, triptorelin, buserelin, histrelin, leuprolide) achieve comparable testosterone suppression to ≤50 ng/dL within one month and ≤20 ng/dL within three months 6

• Goserelin demonstrates superior maintenance of testosterone ≤50 ng/dL compared to leuprolide and has lower incidence of testosterone escape compared to buserelin 6

• Leuprolide remains the most commonly prescribed LHRH agonist and serves as the backbone for most multimodal therapy concepts 3

Critical Monitoring

• Maintain castrate serum testosterone levels (<50 ng/dL) throughout all treatment phases, even when adding additional therapies for castration-resistant disease 7

• PSA monitoring may be performed but has not been shown to correlate with clinical benefit in individual patients 8

• Regular assessment for ADT-related adverse effects including hot flushes, fatigue, sexual dysfunction, cardiovascular effects, and metabolic changes is essential 1

Common Pitfalls to Avoid

• Never discontinue ADT when adding therapies for castration-resistant disease—maintaining castrate testosterone levels remains essential 7

• Do not forget antiandrogen coverage when initiating LHRH agonists in patients with high tumor burden or symptomatic disease 2

• Avoid steroidal antiandrogens as monotherapy due to inferior outcomes and hepatotoxicity risk 1

• Do not administer abiraterone with food—systemic exposure increases 5-10 fold with meals, significantly increasing toxicity risk 8