Are there any available androgen deprivation therapies (ADT) for managing advanced prostate cancer?

Available Androgen Deprivation Therapies for Advanced Prostate Cancer

Yes, multiple androgen deprivation therapy (ADT) options are available and represent the standard first-line systemic treatment for advanced prostate cancer, including bilateral orchiectomy, LHRH agonists (leuprolide), LHRH antagonists (degarelix), and oral GnRH antagonists (relugolix). 1

Standard ADT Modalities

Surgical Castration

• Bilateral orchiectomy provides permanent testosterone suppression and is the most cost-effective option, avoiding ongoing medication costs and compliance issues 1
• Associated with lower risk of fracture, peripheral arterial disease, and cardiac complications compared to LHRH agonists in metastatic disease 2
• More commonly used in developing countries due to cost considerations 2

Medical Castration Options

LHRH Agonists (e.g., Leuprolide):

• Achieve equivalent survival outcomes to surgical castration 1
• Require concurrent antiandrogen coverage for 3-4 weeks to prevent testosterone flare 1
• Represent the most common ADT approach in economically developed countries 2

LHRH Antagonists (e.g., Degarelix):

• Reduce testosterone and PSA levels more rapidly than LHRH agonists without testosterone flare 3
• Efficacy likely equivalent to LHRH agonists for testosterone suppression 4

Oral GnRH Antagonist (Relugolix):

• Provides rapid testosterone suppression without flare 4
• May have improved cardiovascular safety profile compared to LHRH agonists, though this finding requires caution as it derives from secondary subgroup analyses 4

Enhanced Treatment Strategies

Combined Androgen Blockade (CAB)

• LHRH agonist plus nonsteroidal antiandrogen (bicalutamide or flutamide) provides a 3-5% overall survival advantage compared to castration alone when less effective steroidal antiandrogens are excluded 2
• Recommended for patients willing to accept increased side effects for modest survival gain, particularly those with high-volume metastatic disease 1
• Half of expert panelists did not routinely recommend CAB, with 35% recommending it only in selected patients 2

Antiandrogen Monotherapy

• Bicalutamide monotherapy as adjuvant therapy after primary treatment is not supported by evidence 2
• FDA labeling for bicalutamide indicates use in combination with LHRH analog for metastatic prostate cancer 5
• Flutamide demonstrates potent antiandrogenic effects by inhibiting androgen uptake and nuclear binding 6

Treatment Administration Considerations

Continuous vs. Intermittent ADT

• Continuous ADT is recommended over intermittent ADT for metastatic hormone-naïve prostate cancer 1
• The SWOG 9346 trial failed to demonstrate non-inferiority of intermittent ADT, with median OS of 5.8 years for continuous vs. 5.1 years for intermittent therapy 2
• Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic disease after radical prostatectomy or radiation therapy 2
• 94% of expert consensus panelists would discuss intermittent ADT option in metastatic patients achieving adequate PSA decline (below 4 ng/mL after 6 months) 2

Timing of ADT Initiation

• Early 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
• Primary ADT as monotherapy for nonmetastatic disease has not shown survival benefit and is not recommended 7
• No clear evidence supports ADT for biochemical recurrence without metastatic disease, though this remains a common practice 2, 8

Critical Monitoring Requirements

Testosterone Suppression

• Castrate levels of serum testosterone (<50 ng/dL or <1.7 nmol/L) must be achieved and maintained, as low nadir testosterone levels correlate with improved cause-specific survival 2
• Maintain castrate testosterone levels throughout all treatment phases, even when adding therapies for castration-resistant disease 1

Adverse Effect Surveillance

• Monitor for hot flashes (53% incidence), the most frequent adverse reaction with ADT plus LHRH analog 5
• Assess glucose tolerance regularly, as GnRH agonists reduce glucose tolerance and may manifest as diabetes 5
• Monitor for gynecomastia and breast pain (up to 38-39% with bicalutamide 150mg) 5
• For bicalutamide: measure serum transaminases before treatment, at regular intervals for first 4 months, then periodically 5
• Discontinue bicalutamide immediately if jaundice develops or ALT rises above 2x upper limit of normal 5
• For patients on coumarin anticoagulants with bicalutamide, closely monitor PT/INR due to risk of excessive prolongation and serious bleeding 5

Common Pitfalls to Avoid

• Do not use ADT as primary monotherapy for early-stage, low-risk disease, especially in elderly patients, as no 15-year survival benefit exists compared to observation 2
• Avoid initiating LHRH agonists without antiandrogen coverage to prevent testosterone flare 1
• Do not assume intermittent ADT is equivalent to continuous ADT in metastatic disease based on meta-analyses alone; the definitive SWOG trial showed non-inferiority was not achieved 2
• Recognize that ADT adverse effects include decreased libido, impotence, hot flashes, osteopenia with fracture risk, metabolic alterations, and cognitive/mood changes 8
• Consider cardiovascular disease risk, diabetes risk, and skeletal complications when selecting ADT modality, as these may affect mortality 7