ANDROGEN DEPRIVATION
THERAPY (ADT)
ADT reduces testosterone to castrate levels — suppressing the androgen signalling that drives prostate cancer cell survival at every disease stage. It is the most universally used systemic treatment in prostate cancer and the platform onto which all newer hormonal agents are built.
analyticsAt a Glance
- check_circleADT achieves castrate testosterone levels (<50 ng/dL or 1.7 nmol/L) in >95% of patients within 3–4 weeks of initiation
- check_circleGnRH agonists (goserelin, leuprolide, triptorelin) and antagonists (degarelix, relugolix) are the primary pharmacological methods — surgical orchiectomy is the permanent alternative
- check_circleContinuous ADT for metastatic disease; intermittent ADT may be appropriate for selected patients to reduce cumulative toxicity
- check_circleBone loss, metabolic syndrome, cardiovascular risk, and sexual dysfunction are the primary long-term adverse effects requiring proactive monitoring
How ADT Works: The Androgen Axis in Prostate Cancer
Testosterone — produced primarily in the testes (95%) and adrenal glands (5%) — binds to the androgen receptor (AR) inside prostate cancer cells. This triggers AR translocation to the nucleus, where it drives transcription of genes that promote cell survival, proliferation, and PSA production. ADT interrupts this axis — either by preventing testosterone production or by blocking its receptor — depriving cancer cells of their primary growth signal.
“ADT does not cure prostate cancer — it removes the growth signal that most prostate cancer cells depend on. The cancer typically responds for months to years before finding new ways to activate the androgen receptor despite low testosterone.”
The HPG Axis and How GnRH Agents Work
The hypothalamus releases GnRH in pulses, signalling the pituitary to release LH and FSH, which stimulate testicular testosterone production. GnRH agonists initially stimulate LH release (causing a testosterone flare in the first 1–2 weeks) but then downregulate pituitary GnRH receptors — suppressing LH and testosterone to castrate levels within 3–4 weeks. GnRH antagonists (degarelix, relugolix) directly block GnRH receptors, achieving faster castration without the initial testosterone flare.
Castrate Testosterone: The Therapeutic Target
The therapeutic goal of ADT is testosterone below 50 ng/dL (1.7 nmol/L) — the castrate level historically defined by the nadir achievable with surgical orchiectomy. Modern assays can reliably measure below 20 ng/dL, and 'modern' castrate is sometimes defined as <20 ng/dL. Patients who fail to achieve castrate levels on GnRH agonists ('non-castrate') have significantly worse outcomes and require agent change or orchiectomy.
ADT Methods: GnRH Agonists, Antagonists, and Surgical Orchiectomy
Three principal methods achieve medical or surgical castration — each with different administration, onset, testosterone flare profile, and practical considerations.
| Method | Agents / Examples | Mechanism | Testosterone Flare? | Castration Onset | Key Advantage |
|---|---|---|---|---|---|
| GnRH Agonists | Goserelin (Zoladex), Leuprolide (Lupron/Eligard), Triptorelin (Decapeptyl) | Pituitary downregulation after initial stimulation | Yes — first 1–2 weeks; co-prescribe anti-androgen (bicalutamide 50 mg) for 2–4 weeks to block flare in metastatic disease | 3–4 weeks to castrate level | |
| GnRH Antagonists | Degarelix (Firmagon); Relugolix (Orgovyx — oral) | Direct GnRH receptor blockade — no initial stimulation | No — immediate testosterone suppression | 3–5 days to castrate level | |
| Surgical Orchiectomy | Bilateral orchiectomy (removal of both testes) | Permanent removal of primary testosterone source | No | Immediate — hours | |
| Anti-androgens (non-castrating) | Bicalutamide, flutamide (older agents) | AR blockade at receptor level without testosterone suppression | No — testosterone rises | Immediate AR blockade but testosterone not suppressed |
When ADT Is Used: Disease Stages and Clinical Contexts
ADT is used across the prostate cancer disease spectrum — from early biochemical recurrence after radical treatment to metastatic castration-resistant disease.
| Disease Stage / Context | ADT Role | Combination Partners | Duration |
|---|---|---|---|
| Locally advanced (T3/T4, N+, high-risk localised) | Combined with radiotherapy — improves OS (RTOG 85-31, D'Amico data) | External beam radiotherapy × 2–3 years ADT; brachytherapy + short-course ADT | 2–3 years neoadjuvant/adjuvant ADT with RT |
| Biochemical recurrence post-surgery/RT (PSA only) | Salvage ADT when PSA rise is rapid (PSADT <10 months) or imaging shows disease | Observation vs early ADT — intermittent ADT option | Intermittent or continuous; duration guided by PSA response and PSADT |
| Metastatic hormone-sensitive (mHSPC — M1 at diagnosis or at recurrence) | ADT is the backbone — all systemic therapy builds on it | ADT + docetaxel (CHAARTED/STAMPEDE); ADT + abiraterone (LATITUDE); ADT + enzalutamide (ENZAMET/ARCHES); ADT + apalutamide (TITAN) | Continuous — until progression to CRPC |
| Locally advanced N1 post-prostatectomy (pN+) | ADT + RT for pN+ disease — EORTC 30846 supports long-term benefit | Radiotherapy to pelvis + long-term ADT ≥2 years | 2+ years |
| Castration-resistant (CRPC) | ADT continued throughout CRPC — testosterone suppression maintained even after enzalutamide/abiraterone added | Enzalutamide, abiraterone, docetaxel, cabazitaxel, olaparib (BRCA), lutetium-PSMA | Indefinite — lifelong castration maintenance |
Starting ADT: What Happens in the First Weeks
The first 4–6 weeks of ADT are the most important for confirming adequate testosterone suppression and managing the initial side effects.
- 1
Baseline Assessment Before Starting
Before ADT initiation: testosterone level, PSA, LFTs, fasting glucose, HbA1c, lipid profile, bone density (DEXA), blood pressure, and weight — establishing baselines for all parameters that ADT will affect over time.
- 2
Testosterone Flare Warning (GnRH Agonists)
If starting a GnRH agonist in a patient with metastatic bone disease or symptomatic disease: prescribe bicalutamide 50 mg daily starting 3 days before the first GnRH agonist injection and continuing for 4 weeks to block the testosterone flare effect. Flare can cause bone pain flare or, rarely, spinal cord compression.
- 3
First Injection or Tablet
GnRH agonist: monthly (leuprolide 7.5 mg or goserelin 3.6 mg) or 3-monthly (leuprolide 22.5 mg or goserelin 10.8 mg) depot injection. Relugolix: 360 mg loading dose Day 1, then 120 mg daily. Degarelix: 240 mg (two 120 mg injections) loading dose, then 80 mg monthly.
- 4
PSA at 4 Weeks
PSA should begin falling within 4 weeks of ADT initiation in androgen-sensitive disease. A falling PSA confirms androgenic suppression is working. Testosterone confirmation at 4–6 weeks (target <50 ng/dL).
- 5
Hot Flush Management from Week 1
Hot flushes begin within 1–4 weeks of achieving castrate testosterone. Venlafaxine 75 mg or medroxyprogesterone acetate 20 mg are the most evidence-based pharmacological options. Cyproterone acetate 100 mg is highly effective but may have hepatotoxicity risk with chronic use.
ADT: Key Clinical Numbers
Reference figures for clinical practice and patient conversations about ADT.
- <50 ng/dLCastrate testosterone target levelThe traditional definition of medical castration — equivalent to the nadir achieved by surgical orchiectomy. Modern assays target <20 ng/dL at some centres.
- 3–5 daysTime to castration with GnRH antagonists (degarelix, relugolix)Compared to 3–4 weeks with GnRH agonists — the primary clinical advantage of antagonists in urgent or high-disease-burden situations.
- 8–10%Bone mineral density loss per year on continuous ADTAmong the most significant preventable long-term ADT complications — addressed by bisphosphonates (zoledronic acid) or denosumab and calcium/vitamin D supplementation.
- 80%Of patients with PSA response to first-line ADTThe vast majority of hormone-sensitive prostate cancers respond initially to ADT — median response duration depends on disease volume and prior treatment.
More from the Hormone Therapy Resource Library
Continue exploring ADT and advanced prostate cancer treatment.
- Enzalutamide vs Abiraterone vs Darolutamide: Comparing Next-Generation Hormonal Therapies
- ADT Side Effects: Managing Bone Loss, Hot Flushes, and Fatigue
- How Long Should I Take Hormone Therapy? Duration Decisions
- What Is Hormone Therapy for Cancer and How Does It Work?
- Hormone Therapy for Prostate Cancer — Complete Guide
- PSMA-Targeted Therapy for Prostate Cancer
Frequently Asked Questions
Common questions from patients starting or considering androgen deprivation therapy.
About ADT
Is relugolix (Orgovyx) better than goserelin or leuprolide?
Relugolix is the first oral GnRH antagonist and offers several advantages over injectable GnRH agonists: no testosterone flare, faster castration onset (3–5 days vs 3–4 weeks), and in the HERO trial, significantly lower rates of major adverse cardiovascular events — a 54% relative risk reduction. For patients with pre-existing cardiovascular disease or at high cardiovascular risk, relugolix is preferred. The practical advantage is oral daily dosing (avoiding monthly injections), and the reversibility profile is faster than GnRH agonists. Limitations include the need for daily pill compliance and, in some jurisdictions, higher cost or limited insurance coverage. Relugolix is not yet available in all countries — check local availability with your oncologist or CancerFax.
My doctor mentioned intermittent ADT — is this as effective as continuous therapy?
Intermittent ADT — cycling on and off treatment based on PSA response — has been studied in several randomised trials. In patients with non-metastatic biochemical recurrence, intermittent ADT appears non-inferior to continuous ADT for overall survival, with meaningful improvements in quality of life (sexual function, hot flushes, energy) during the off-treatment intervals. For metastatic hormone-sensitive disease, intermittent ADT is more controversial — the SWOG 9346 trial showed it was potentially inferior to continuous ADT for overall survival in the metastatic setting, particularly in patients with extensive bone disease. The decision should be made individually based on disease stage, PSA nadir, and the patient's priorities regarding quality of life versus the theoretical risk of more rapid resistance development.
I have heard ADT causes heart problems — is this true?
ADT is associated with a small but real increase in cardiovascular risk — including atrial fibrillation, QTc prolongation (particularly with some anti-androgens), and in some studies, an increased risk of myocardial infarction and stroke over long-term use. The mechanisms include insulin resistance, dyslipidaemia, and increases in fat mass. The risk is most relevant for patients with pre-existing cardiovascular disease. Relugolix (oral GnRH antagonist) has demonstrated significantly lower cardiovascular event rates than leuprolide in the HERO trial. For all ADT patients: cardiovascular risk factor management (blood pressure, lipids, glucose, exercise, smoking cessation) is part of standard ADT monitoring — not optional.
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Questions About ADT for Prostate Cancer?
CancerFax connects patients with specialist urological and medical oncologists who can review your PSA trajectory, imaging, and overall health to advise on the most appropriate ADT approach, duration, and monitoring strategy for your specific disease stage.
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified oncologist before making treatment decisions.