Androgen deprivation therapy (ADT) is the backbone of systemic treatment for advanced prostate cancer. Because prostate cancer growth is androgen-driven, blocking the androgen axis — surgically or medically — produces a clinical response in the great majority of men, although the disease eventually becomes castrate-resistant.
Androgen Physiology and the Androgen Receptor
The principal androgen of the prostate is dihydrotestosterone (DHT), converted from testosterone by 5α-reductase. Type 1 is found mainly in non-genital skin and liver (and, to a lesser degree, prostate, testis, and brain); type 2 predominates in the prostate epithelium and other genital tissues, and is also present in liver, breast, hair follicles, and placenta. Functional type 2 enzyme is a prerequisite for normal prostate and external-genital development, and men with inherited 5α-reductase deficiency have minuscule prostatic tissue. DHT binds the androgen receptor (AR) with much higher affinity than testosterone, promoting nuclear translocation of the steroid–receptor complex and activation of androgen response elements. (5α-reductase inhibitors raise serum testosterone — usually within the normal range — and increase intraprostatic testosterone.)
Lack of testosterone is protective, but even hypogonadal men can develop prostate cancer through androgen-independent pathways, and the AR remains central to castrate-resistant progression. The AR is a ligand-inducible transcription factor, and five mechanisms drive castration resistance:
- Hypersensitivity — AR amplification lets even low androgen levels activate the pathway.
- Promiscuity — the AR is activated by non-androgen ligands.
- Outlaw — growth factors (EGF, IGF-1) raise AR activity in the absence of androgen.
- Bypass — parallel survival pathways keep cells alive without androgen.
- Lurker cell — pre-existing epithelial stem cells are selected out by androgen deprivation.
ADT is continued through CRPC because the disease is rarely truly resistant to androgen action — exogenous androgen causes symptomatic tumour flare in 87% of CRPC patients. (The term castrate-resistant is preferred over hormone-refractory.)
Approaches to Androgen-Axis Blockade
Charles Huggins first demonstrated hormonal control of prostate cancer in 1946 (orchiectomy and estrogen lowered serum acid phosphatase in 8 men with metastatic disease; PSA was not discovered until 1979), work that earned the 1966 Nobel Prize. The axis can be blocked at four points:
| Target | Agents |
|---|---|
| Ablate the source | Bilateral orchiectomy |
| Inhibit stimulation (LHRH/LH) | Estrogen, LHRH agonists, LHRH antagonists |
| Inhibit synthesis | Ketoconazole, abiraterone |
| Block the receptor | Cyproterone acetate, flutamide, bicalutamide, enzalutamide, apalutamide, darolutamide |
Surgical Castration and Estrogens
Bilateral orchiectomy reduces testosterone to castrate levels (<50 ng/dL) within 24 hours (>90% reduction) but has largely been replaced by LHRH analogues; subcapsular orchiectomy removes only glandular tissue to avoid an empty scrotum. Estrogen was the first central inhibitor — estradiol is 1,000× more potent than testosterone at suppressing LH/FSH — and diethylstilbestrol (DES) is as effective as surgical castration but limited by cardiovascular toxicity (though it remains the cheapest form of ADT).
LHRH Agonists
As effective as orchiectomy and now the dominant therapy thanks to long-acting depot preparations (e.g. goserelin 10.8 mg SC every 3 months, leuprolide 22.5 mg SC every 3 months, triptorelin). Their drawback is an initial testosterone flare: LH surges up to 10-fold, and the resulting testosterone rise can cause a life-threatening symptom exacerbation. Cover the flare with an anti-androgen (bicalutamide 50 mg daily) for 21–28 days (the flare itself lasts 10–20 days); simultaneous and pre-emptive dosing give similar PSA results. After the surge, phasic pituitary stimulation is lost and testosterone falls to castrate levels.
LHRH Antagonists
These bind LHRH receptors immediately and competitively, dropping LH by 84% within 24 hours and avoiding any surge — so no anti-androgen cover is needed and testosterone falls within 3 days (castrate in 34.5%, 60.5%, and 98.1% of men at days 2, 4, and 28). They are preferred when urgent castration is needed (impending cord compression, severe bone pain) or surgical castration is unsuitable. Agents are the "-lix" drugs (abarelix, cetrorelix, degarelix, relugolix); degarelix was non-inferior to leuprolide at 1 year (Klotz 2008) and, unlike abarelix, causes no systemic allergic reaction.
The oral antagonist relugolix was tested in HERO (Shore 2020; 930 men with relapse after curative treatment, newly diagnosed metastatic hormone-sensitive disease, or advanced localized disease): relugolix 120 mg orally daily was superior to leuprolide for sustained castration at 48 weeks (96.7% vs 88.8%) and halved major cardiovascular events (HR 0.46).
By method, LHRH agonists reduce LH and only partially suppress FSH, LHRH antagonists reduce both LH and FSH, and surgical castration leaves LH and FSH significantly elevated.
Androgen Synthesis Inhibitors
Ketoconazole (historical) is a non-specific CYP450 inhibitor that abolishes adrenal and Leydig-cell steroid synthesis within hours; its effect is immediately reversible, requiring continuous 8-hourly dosing, and it is given with hydrocortisone (20 mg BID). Aminoglutethimide (historical) blocked an early steroidogenic step, acting as a medical adrenalectomy that required cortisone and fludrocortisone replacement.
Abiraterone acetate is an orally active, irreversible inhibitor of CYP17 (both 17,20-lyase and 17α-hydroxylase), blocking androgen synthesis in the testis, adrenals, and tumour itself — more potent than ketoconazole. Blocking 17α-hydroxylase raises mineralocorticoids (deoxycorticosterone, corticosterone) and suppresses cortisol with a compensatory ACTH rise, so it is co-administered with prednisone. Key adverse effects are hypertension, hypokalaemia, and fluid overload (mineralocorticoid excess), plus fatigue, raised lipids, myopathy, and — most seriously — hepatotoxicity (the commonest reason for dose reduction; check LFTs and electrolytes frequently). It is used in CRPC (COU-AA-301 post-docetaxel, COU-AA-302 pre-docetaxel) and hormone-sensitive disease (LATITUDE, STAMPEDE — see Metastatic Hormone-Sensitive Prostate Cancer).
Androgen-Receptor Antagonists
Anti-androgens are steroidal or non-steroidal:
- Steroidal (cyproterone acetate) also suppresses the hypothalamic-pituitary axis, lowering LH and testosterone (by 70–80%); adverse effects are fluid retention, thromboembolism, and hypogonadism.
- Non-steroidal ("-lutamides") block the AR at target tissues and the hypothalamus, raising LH and testosterone (to ~1.5× normal). They cause less hypogonadism and osteoporosis but more cardiovascular risk, and share class toxicities of hepatotoxicity (reversible hepatitis to fulminant failure — monitor LFTs), diarrhoea (worst with flutamide), and gynaecomastia/breast pain (from aromatization of testosterone to estradiol).
| Generation | Agent | Notes |
|---|---|---|
| First | Flutamide | Short half-life, three-times-daily dosing |
| Bicalutamide | Once daily; PK unaffected by age, renal, or moderate hepatic impairment; 150 mg/day monotherapy ≈ castration in metastatic/locally advanced disease, with better sexual interest and physical capacity but more gynaecomastia (66.2%) and breast pain (72.8%) | |
| Nilutamide | ~25% report delayed dark adaptation after bright light | |
| Second | Enzalutamide | Irreversibly binds the AR, blocking androgen binding, nuclear translocation, and DNA binding; contraindicated with a seizure history |
| Apalutamide | Binds the AR ligand-binding domain; contraindicated with a seizure history; adds hypothyroidism and rash | |
| Darolutamide | Low blood–brain-barrier penetration → fewer and less severe toxic effects than the other two |
Shared second-generation toxicities include hypertension, diarrhoea, fatigue, seizures (<1%), falls, and fractures. Their trial programmes:
| Agent | Disease-state trials |
|---|---|
| Enzalutamide | AFFIRM (post-docetaxel mCRPC), PREVAIL (pre-docetaxel mCRPC), PROSPER (M0 CRPC), ENZAMET & ARCHES (M1 CSPC) |
| Apalutamide | SPARTAN (M0 CRPC), TITAN (M1 CSPC) |
| Darolutamide | ARAMIS (M0 CRPC) |
A clinical response to ADT is almost universal; the magnitude and rapidity of the PSA fall are the best predictors of how durable that response will be, and a sluggish response signals a large androgen-refractory population.
Combined Androgen Blockade
Combined androgen blockade (CAB) adds an anti-androgen to castration to also block residual adrenal androgens. In a meta-analysis of 27 trials there was no overall 5-year survival difference (CAB 25.4% vs ADT 23.6%); cyproterone-containing arms did slightly worse (15.4% vs 18.1%, suggesting excess non-cancer deaths), whereas with the non-steroidal anti-androgens flutamide or nilutamide CAB gave a small but significant 3% absolute 5-year survival gain (27.6% vs 24.7%).
Indications and Timing
- Low-risk localized disease — no benefit, and worse overall survival, from primary ADT.
- Locally advanced / asymptomatic metastatic — the role is controversial; in community practice with limited monitoring, immediate ADT improves cancer-specific but not overall survival, while in men unsuitable for local treatment it improves overall but not cancer-specific survival.
- Node-positive — no advantage to immediate ADT in untreated cN+ disease, but a significant survival advantage (2.6-year median OS gain) for immediate ADT in pN+ disease after prostatectomy (ECOG 3886, Messing).
- Symptomatic metastatic disease — ADT is indicated.
The AUA recommends palliative ADT monotherapy only for high-risk localized disease with local symptoms and limited life expectancy, supports ADT for metastatic hormone-sensitive and castrate-resistant disease, and advises against routinely starting ADT for biochemical recurrence without metastases.
Intermittent vs Continuous ADT
Intermittent ADT lengthened the time to androgen-refractory growth in animal models and is intended to improve quality of life. Two trials defined its role:
| Trial | Population | Result |
|---|---|---|
| PR7 (Crook 2012) | Rising PSA after radiotherapy | Intermittent ADT non-inferior for OS (8.8 vs 9.1 yr); better hot flashes, sexual desire, and urinary symptoms (95% CI upper limit 1.22, below the 1.25 non-inferiority margin) |
| SWOG 9346 (Hussain 2013) | Newly diagnosed metastatic | Statistically inconclusive, but median OS numerically worse with intermittent (5.1 vs 5.8 yr); intermittent "may compromise survival" |
Both used an induction period (8 and 7 months) and stopped ADT once PSA fell below 4 ng/mL, managing CRPC continuously; they differed in population and restart thresholds (PSA 10 after radiotherapy vs 20 for metastatic disease). There is no consensus on the ideal schedule, but non-metastatic patients generally tolerate intermittent ADT without compromising oncologic outcomes, whereas metastatic patients should be offered it with caution.
Complications of ADT
The toxicities are broad — a useful mnemonic is "COACH Wants BDSM From Montreal": Cardiovascular disease, Osteoporosis, Anaemia, Cognitive dysfunction, Hot flashes, Weight gain, Breast events, Diabetes, Sexual dysfunction, Muscle-mass loss, Fatigue, and Metabolic effects.
| Complication | Key facts |
|---|---|
| Cardiovascular | Pre-existing heart disease is the key risk factor for MACE; GnRH antagonists carry lower CV risk than agonists (HR 0.44; HERO MACE 3% vs 6%) — consider an antagonist after prior MI/stroke. Nanda (2009): excess mortality only in men with CAD-induced CHF or prior MI |
| Osteoporosis | BMD falls fastest in year 1; ~4 years of ADT pushes the average man into osteopenia (T-score <−1). Shahinian (2005): 5-year fracture risk 19% vs 13%, hospitalization for fracture 5.2% vs 2.4% |
| Anaemia | Normochromic, normocytic; Hb falls 1–2 g/dL (see Corrections note); ~90% on CAB drop ≥10% |
| Cognitive | Possible depression (HR 1.51), dementia (HR 1.21), and Alzheimer's (HR 1.16); causality remains weak |
| Hot flashes | Affect 50–80%; decrease over time |
| Weight / fat | Weight +2.1%, fat mass +8% (subcutaneous), as early as 1 month; may persist 2 years after stopping |
| Breast events | Gynaecomastia (aromatization to estradiol) — most common with anti-androgen monotherapy, rare with LHRH monotherapy or CAB |
| Diabetes | Alibhai (2009): incident diabetes HR 1.16 |
| Sexual | Loss of libido up to 90%; stretched penile length fell 10.76 → 8.05 cm over 15 months; only ~20% maintain any sexual activity |
| Muscle / fatigue | Reduced grip strength, gait speed, and aerobic fitness; fatigue is multifactorial |
| Metabolic | Insulin resistance, glucose intolerance, raised triglycerides/LDL/total cholesterol, and metabolic syndrome (Braga-Basaria 2006) |
The cardiovascular evidence is mixed — observational studies and randomized-trial meta-analyses agree on increased non-fatal cardiovascular disease but disagree on cardiovascular mortality, MI, and stroke. Among the agents, enzalutamide raises hypertension (but not cardiac events), while abiraterone is associated with more cardiac events, atrial tachyarrhythmia, and heart failure. (PRONOUNCE and RADICAL-PC are addressing cardiac outcomes prospectively.)
Monitoring and Prevention on ADT
Before starting ADT (2021 CUA guidance), assess cardiometabolic and bone risk:
- Cardiometabolic — history of MACE, cardiac risk factors, and prior VTE/stroke; measure BP, weight, waist circumference, and BMI; screen for diabetes (fasting glucose, OGTT, or HbA1c) and check a lipid profile; refer to cardiology after prior MI or stroke.
- Bone — falls-risk and height; check calcium and 25-hydroxyvitamin D; obtain a DXA and calculate the 10-year fracture risk (FRAX).
On treatment:
- Cardiometabolic — supervised resistance plus aerobic exercise (superior to self-directed programmes and beneficial across physical, functional, endocrine, and quality-of-life domains); target BP <130/80; repeat diabetes and lipid screening every 6–12 months.
- Bone — calcium 1,200 mg/day total and vitamin D 800–2,000 IU/day; bisphosphonates (zoledronic acid, alendronate, pamidronate) for osteoporosis, prior fragility fracture, or moderate/high fracture risk. The 2020 CUA CSPC guideline recommends vitamin D and calcium for all men on ADT, with bone-targeted therapy (zoledronic acid 5 mg yearly, alendronate 70 mg weekly, or denosumab 60 mg every 6 months) for those at high fracture risk; in CRPC with bone metastases, denosumab or zoledronic acid is given every 4 weeks. Repeat DXA every 1–3 years according to risk.
- Hot flashes — avoid triggers; options (none formally approved) include medroxyprogesterone 20 mg daily, megestrol 20 mg BID (monitor for disease progression), cyproterone 50–100 mg daily, gabapentin 900 mg daily, and venlafaxine 75 mg daily (cyproterone and medroxyprogesterone outperformed venlafaxine in Irani 2010); intermittent ADT and acupuncture may help.
- Breast events — tamoxifen is more effective than radiotherapy (10–12 Gy) for both prophylaxis and treatment (radiotherapy has no benefit once gynaecomastia is established); routine prophylaxis is not recommended.
- Other — exercise for fatigue; hematology referral for severe or unexpectedly steep anaemia; sex-therapy referral and PDE5 inhibitors for sexual dysfunction; monitor for cognitive decline and depression; consider intermittent ADT to improve quality of life.
Self-Test
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What are the four therapeutic approaches to androgen-axis blockade? Inhibit androgen synthesis, ablate androgen sources, inhibit LHRH/LH release, and block the androgen receptor.
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How quickly does bilateral orchiectomy achieve castrate testosterone? Within 24 hours.
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What are the advantages of LHRH antagonists over agonists? No anti-androgen cover is needed (no LH surge) and testosterone falls quickly.
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What happens to LH and FSH after surgical castration, an LHRH agonist, and an LHRH antagonist? Surgical castration → elevated LH and FSH; agonist → suppressed LH, partially suppressed FSH; antagonist → suppressed LH and FSH.
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Compare steroidal and non-steroidal anti-androgens. Steroidal (cyproterone) lowers LH and testosterone and causes fluid retention, thromboembolism, and hypogonadism; non-steroidal raises LH and testosterone and causes hepatotoxicity, GI toxicity, and gynaecomastia/mastodynia.
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List key adverse effects of enzalutamide, apalutamide, and abiraterone. Enzalutamide — hypertension, fatigue, diarrhoea, seizures, falls, fracture, hot flashes. Apalutamide — the same first six plus hypothyroidism, rash, raised cholesterol, hyperglycaemia, and anaemia. Abiraterone — hypertension, fatigue, fluid overload, hypokalaemia, hepatotoxicity, myopathy/rhabdomyolysis, and raised lipids.
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What are the major adverse effects of ADT? Recalled by "COACH Wants BDSM From Montreal": cardiovascular disease, osteoporosis, anaemia, cognitive dysfunction, hot flashes, weight gain, breast events, diabetes, sexual dysfunction, muscle-mass loss, fatigue, and metabolic effects.