Androgen Deprivation Therapy

Androgen deprivation therapy lowers testosterone to castrate levels or blocks the androgen receptor, starving prostate cancer cells of the stimulus for growth. It is the backbone of treatment for advanced and metastatic prostate cancer and is given with radiotherapy in high-risk localised disease.

Classification. Surgical (bilateral orchidectomy); GnRH agonists (goserelin, leuprorelin, triptorelin); GnRH antagonists (degarelix, relugolix); first-generation antiandrogens (bicalutamide, flutamide); second-generation androgen receptor inhibitors (enzalutamide, apalutamide, darolutamide); and androgen synthesis inhibitor (abiraterone).

Pharmacokinetics. GnRH agonists first stimulate the pituitary and cause a testosterone surge for 1 to 3 weeks before castration is reached at about 4 weeks; antagonists lower testosterone within days with no surge.

• Goserelin 3.6 mg subcutaneously every 28 days, 10.8 mg every 12 weeks; leuprorelin 3.75 mg monthly, 11.25 mg every 3 months, or 22.5 mg every 3 months.
• Degarelix 240 mg subcutaneously loading dose, then 80 mg monthly.
• Relugolix 360 mg orally on day 1, then 120 mg once daily.
• Bicalutamide 50 mg daily with a GnRH agonist, or 150 mg daily monotherapy (non-metastatic, selected); flare cover 50 mg daily for 2 to 4 weeks starting 7 days before the first agonist injection.
• Abiraterone 1,000 mg daily on an empty stomach with prednisolone 5 mg daily (or 250 mg with food).
• Enzalutamide 160 mg daily; apalutamide 240 mg daily; darolutamide 600 mg twice daily with food.
• Bilateral orchidectomy: the lowest-cost, definitive option and appropriate where injections are unavailable.

Differences. Antagonists avoid flare and are preferred in spinal metastases or impending cord compression; agonists need antiandrogen cover.

• Localised high-risk disease with radiotherapy: 2 to 3 years of androgen deprivation; 4 to 6 months in intermediate risk.
• Biochemical recurrence or metastatic hormone-sensitive disease: continuous androgen deprivation with an androgen receptor inhibitor or abiraterone, with docetaxel in high-volume disease.
• Castration-resistant disease: continue androgen deprivation (castrate testosterone under 50 ng/dL, 1.7 nmol/L) and add enzalutamide, abiraterone, darolutamide or docetaxel.
• Pre-treatment: baseline PSA, testosterone, liver enzymes, bone density, glucose or HbA1c, lipids, blood pressure, and ECG (QT with some drugs).
• Intermittent therapy: reserved for selected patients; continuous therapy is usual.

Selection. Consider orchidectomy where injectable drugs are costly or unreliable; use antagonists when a flare is dangerous.

Contraindications. Pregnancy (androgen receptor inhibitors, abiraterone); severe liver disease (abiraterone, flutamide); seizure history (enzalutamide, caution).

Adverse effects. Hot flushes, loss of libido, erectile dysfunction, fatigue, anaemia, gynaecomastia, loss of muscle mass, osteoporosis and fractures, insulin resistance and diabetes, hypercholesterolaemia, cardiovascular events, depression, cognitive effects, and QT prolongation. Abiraterone: hypertension, hypokalaemia and fluid retention, hepatotoxicity. Enzalutamide and apalutamide: fatigue, seizures, falls, rash.

Interactions. Rifampicin and phenytoin lower enzalutamide, apalutamide and abiraterone levels; ritonavir-boosted regimens and azoles raise them; enzalutamide induces CYP3A4 and lowers warfarin effect; abiraterone inhibits CYP2D6; avoid QT-prolonging drugs.

Special groups.

• Pregnancy: avoid; partners need contraception.
• Older adults: falls and cognitive effects.
• Kidney impairment: no adjustment for most; degarelix caution in severe.
• Liver impairment: reduce abiraterone to 250 mg in moderate disease; avoid in severe.

Monitoring. PSA and testosterone every 3 to 6 months; blood pressure, potassium and liver enzymes monthly for 3 months then every 3 months with abiraterone; bone density every 1 to 2 years with calcium, vitamin D and a bisphosphonate or denosumab; lipids and glucose annually; exercise and weight management.

Referral and escalation. Back pain, leg weakness or urinary retention (cord compression: dexamethasone 8 to 16 mg and urgent imaging), pathological fracture, rising PSA with castrate testosterone, and adrenal insufficiency need urgent care.