Prostate Cancer and Androgen Deprivation: Cutting Off the Fuel

One idea: the cancer runs on testosterone

Prostate cancer is an androgen-driven disease. Testosterone — and its more potent tissue form dihydrotestosterone (DHT) — binds the androgen receptor (Androgen receptor) inside prostate cells and switches on the genes that make them grow and divide. Cancerous prostate cells keep that dependence: cut the androgen supply and most of them shrink and die. So the backbone of treatment for advanced disease is not to poison the cell but to starve it — androgen-deprivation therapy (Androgen deprivation therapy, ADT). This is exactly the mirror image of endocrine therapy in breast cancer, where we block estrogen; here we block androgen. Same strategy, opposite hormone. (The androgen physiology itself — the hypothalamic–pituitary–gonadal axis — is covered in the Endocrine sex-hormones section; this chapter is what happens when you deliberately break that axis.)

There are, in principle, only a handful of places to cut the fuel line. You can silence the brain's signal to the testes (GnRH agonists and antagonists). You can block the receptor so testosterone arrives but can't be read (anti-androgens). You can shut down androgen synthesis at its source anywhere in the body (abiraterone). And when the tumour learns to survive on trace amounts, you fall back on chemotherapy and newer targeted agents. Each of the following classes is one point on that pipeline.

GnRH agonists: the paradox of the flare

The most counter-intuitive drugs in the whole chapter. Normally the hypothalamus releases GnRH in pulses, and those pulses tell the pituitary to release LH, which tells the testes to make testosterone. GnRH (LHRH) agonists — goserelin and leuprolide — flood the pituitary with a constant, non-pulsatile signal. At first this backfires: the pituitary is overstimulated and testosterone SURGES for the first week or two — the testosterone 'flare'. Only after continuous stimulation does the pituitary down-regulate its receptors, LH collapses, and testosterone falls to castrate levels. So an agonist reaches the goal — but takes a dangerous detour on the way.

GnRH antagonists: castration with no detour

If the flare is the agonist's flaw, the antagonists simply remove it. GnRH antagonists — degarelix (injected) and relugolix (an oral tablet) — block the pituitary receptor directly, from the first dose. There is no initial surge: testosterone falls to castrate levels within days, with NO flare. That makes an antagonist the cleaner choice when you cannot afford a surge at all — a man with a heavy bone-metastasis burden or an impending cord compression — and relugolix adds the convenience of a pill instead of a depot injection.

Anti-androgens: blindfolding the receptor

The second point on the pipeline is the receptor itself. Anti-androgens are androgen-receptor blockers: testosterone still circulates, but it can't dock and switch on the growth genes. The older, milder one is bicalutamide — cheap, useful for flare cover and as an add-on. The revolution came from the potent second-generation blockers: enzalutamide, apalutamide and darolutamide. These bind the receptor far more tightly, and enzalutamide also blocks the receptor's movement into the nucleus and its binding to DNA — so it works even when the tumour has adapted to very low testosterone. They are now mainstays in advanced and castration-resistant disease.

Abiraterone: cutting off synthesis everywhere

GnRH drugs stop the testes, but the adrenal glands — and the tumour itself — can still make small amounts of androgen, enough to keep a resistant cancer alive. Abiraterone closes that door. It inhibits CYP17 (17α-hydroxylase/17,20-lyase), the enzyme that any tissue needs to build androgens from cholesterol. Blocking CYP17 shuts down androgen production in the testes, the adrenals AND the tumour — a far deeper deprivation than castration alone. This is why abiraterone works in disease that has already outgrown simple ADT.

When castration stops working

Eventually many cancers progress despite castrate testosterone — castration-resistant prostate cancer (CRPC). The pipeline branches. Chemotherapy with a taxane — docetaxel first, then cabazitaxel — attacks the dividing cell directly by jamming its microtubules (the same microtubule-agents chapter that covers the taxanes). For men whose tumour carries a BRCA1/2 or other DNA-repair mutation, PARP inhibitors (e.g. olaparib) exploit that defect — the precision-oncology idea developed in the kinase-inhibitors and precision-oncology chapters. And for painful bone metastases specifically, radium-223, a bone-seeking alpha-emitter, deposits radiation exactly where the cancer sits in the skeleton, easing pain and prolonging life.

The price of an empty tank: low-testosterone effects

Every drug in this chapter produces the same physiology: a man with almost no testosterone. So they share a common side-effect signature, and it is the everyday reality your patient lives with. Hot flushes and sweats. Loss of libido and erectile dysfunction. Osteoporosis with a real fracture risk over years of therapy — which is why long-term ADT demands bone protection (calcium, vitamin D, and a bone-targeted agent such as a bisphosphonate or denosumab, covered in the Endocrine bone chapter). Loss of muscle mass and strength. Metabolic and cardiovascular effects — weight gain, insulin resistance, dyslipidaemia and increased cardiovascular risk. And gynaecomastia — breast tenderness and enlargement. None of these are footnotes; managing them is half of good prostate-cancer care.