Prostate Cancer: Androgen Deprivation and Beyond

The addiction: an androgen-driven cancer

To understand the drugs, follow the hormone. The prostate is an androgen-dependent organ, and so, at first, is its cancer. The hypothalamus releases GnRH in pulses; this drives the pituitary to secrete LH; LH tells the testes to make testosterone. Inside the prostate, the enzyme 5-alpha-reductase converts testosterone into dihydrotestosterone (DHT), a more potent androgen that binds the androgen receptor and switches on the genes for growth. A smaller but real fraction of androgen also comes from the adrenal glands, and — importantly — from the tumour itself, which can make its own. The full physiology of this HPG axis and of testosterone/DHT is taught in the Endocrine section; here we simply weaponise the pathway in reverse. Cut off the androgen signal at any level and most prostate cancers shrink.

ADT part 1 — switching off the brain: GnRH agonists and the flare

The counter-intuitive workhorses of medical castration are the GnRH agonists — goserelin and leuprorelin (leuprolide), given as depot injections. Normally the pituitary answers GnRH only in pulses; flood it with a continuous agonist and, after an initial burst, it desensitises and downregulates its GnRH receptors. LH then collapses, the testes go quiet, and testosterone falls to castrate levels within two to four weeks. The paradox is that first burst: for the first days to two weeks the drug actually raises testosterone — the testosterone flare — which can transiently worsen bone pain, worsen urinary obstruction, or, most dangerously, precipitate spinal cord compression in a man with vertebral metastases. The fix is to give an anti-androgen (see below) starting a few days before, and continued for two to three weeks, to blindfold the receptor while the flare passes. This flare is the same pharmacology students meet in the Endometriosis chapter, where a GnRH agonist first stimulates before it suppresses.

ADT part 2 — no flare: GnRH antagonists

GnRH antagonists sidestep the flare entirely. Instead of overstimulating the receptor, they block it directly, so LH and testosterone drop immediately with no initial surge. Degarelix is the injectable option; relugolix is an oral GnRH antagonist — a once-daily tablet — that achieves rapid castration and, when stopped, a faster testosterone recovery than depot agonists. Antagonists are especially useful when a fast fall matters and you cannot risk a flare: impending cord compression, severe bony disease, or bladder-outflow obstruction. Some data also suggest fewer cardiovascular events with antagonists than agonists, which matters because these men are often older with heart disease.

ADT part 3 — blocking the receptor: anti-androgens

Anti-androgens work at the far end of the pipeline: they bind the androgen receptor and stop testosterone and DHT from activating it. The first-generation agents — bicalutamide and flutamide — are competitive receptor blockers, used mainly for flare cover at the start of a GnRH agonist and sometimes as monotherapy in men wanting to preserve some sexual function. The second-generation anti-androgens are a different order of drug: enzalutamide, apalutamide and darolutamide bind the receptor far more tightly, also block its movement into the nucleus and its binding to DNA, and prolong survival even when the cancer has become castration-resistant. They are a pillar of modern advanced-disease treatment. Their trade-offs sit in the central nervous system — fatigue, falls, and (for enzalutamide and apalutamide) a small seizure risk — with darolutamide crossing into the brain the least.

ADT part 4 — cutting the supply: abiraterone

GnRH drugs and orchidectomy switch off the testes, but the adrenals and the tumour itself keep making androgens. Abiraterone closes that loophole. It inhibits CYP17, the key enzyme in androgen biosynthesis, shutting down androgen production everywhere it happens — testes, adrenal glands and tumour tissue. The catch is a predictable side effect of blocking that enzyme: upstream steroid precursors are shunted toward mineralocorticoids, causing a syndrome of fluid retention, hypertension and low potassium. So abiraterone is always co-prescribed with low-dose prednisolone (a corticosteroid), which replaces the cortisol the block also lowers and switches off the drive to overproduce mineralocorticoids. This CYP17 biochemistry is the same enzyme step covered in the Endocrine/adrenal-steroid pathway, applied here as cancer therapy.

The price of castration: side effects of hypo-androgenism

Take away a man's testosterone and the whole body notices. The very effect that treats the cancer is what causes the harm: a hypogonadal state. The commonest complaints are hot flushes, loss of libido and erectile dysfunction, fatigue, and gynaecomastia (breast tenderness and enlargement, especially with anti-androgen monotherapy). Over the longer term, the damage is metabolic and skeletal: loss of bone density leading to osteoporosis and fractures, loss of muscle with weight gain, insulin resistance and worsening lipids, and an increased cardiovascular risk. Bone health matters enough that men on long-term ADT need calcium, vitamin D and, where risk is high, a bone-protecting agent such as a bisphosphonate or denosumab — the same osteoporosis pharmacology taught in the Endocrine/Bone section, applied to a drug-induced hypogonadism. Hot flushes and gynaecomastia can be managed symptomatically; the metabolic and cardiovascular risks are managed by treating blood pressure, lipids and glucose actively and keeping the man moving.

Beyond ADT: castration-resistant disease

When PSA rises despite castrate testosterone, the cancer is castration-resistant, and the toolbox widens. Chemotherapy re-enters — the taxanes docetaxel and, later, cabazitaxel, which stabilise microtubules and stop cell division; their mechanisms belong to the Oncology section and are not re-taught here, but note that docetaxel is increasingly moved earlier, given alongside ADT, in men with high-volume metastatic disease. For cancer that has spread to bone, radium-223 is an alpha-emitting radioisotope that behaves like calcium, homing to areas of high bone turnover and delivering short-range radiation precisely where the metastases live, prolonging life and reducing skeletal events. For men whose tumours carry BRCA or other homologous-recombination-repair (HRR) mutations, a PARP inhibitor such as olaparib exploits synthetic lethality — the same DNA-repair logic taught in the Oncology chapter. And the newest arm is PSMA-targeted radioligand therapy: lutetium-177 (¹⁷⁷Lu-PSMA-617) links a beta-emitting isotope to a molecule that binds prostate-specific membrane antigen, delivering radiation to PSMA-expressing cells wherever they hide. Sequencing all of this — and the taxane mechanisms — is shared with Oncology; the androgen axis is simply where genitourinary and oncology pharmacology meet.