Androgen deprivation therapy (ADT) uses several classes of drugs to lower testosterone to very low levels, typically below 50 ng/dL. The main categories include GnRH agonists, GnRH antagonists, androgen receptor inhibitors, and drugs that block testosterone production outside the testes. Most people on ADT receive one or more of these in combination, depending on cancer stage and treatment goals.
GnRH Agonists
GnRH agonists are the most widely used drugs in ADT. They work by overstimulating the pituitary gland, which initially causes a brief spike in testosterone before the receptors become desensitized and shut down. Once that desensitization takes hold, testosterone drops to castrate levels. The most commonly prescribed GnRH agonists are leuprolide (Lupron), goserelin (Zoladex), and triptorelin (Trelstar).
These drugs are given as injections or implants, with formulations lasting anywhere from one month to a full year. The convenience of infrequent dosing is a major advantage, but the initial testosterone spike, known as a “flare,” can temporarily worsen symptoms in men with advanced disease. To prevent this, doctors typically prescribe a short course of an older anti-androgen called bicalutamide, started at least seven days before or alongside the first agonist injection. Even after that initial flare period, smaller testosterone surges can still occur with repeat injections in roughly 18% to 27% of patients on goserelin.
GnRH Antagonists
GnRH antagonists take the opposite approach. Instead of overstimulating the pituitary, they directly block GnRH receptors. This produces a rapid drop in testosterone without any flare, which makes them especially useful for men whose cancer is pressing on the spine or urinary tract, where even a brief hormone surge could cause serious problems.
Two GnRH antagonists are currently available. Degarelix (Firmagon) is given as a monthly injection. Relugolix (Orgovyx) is the only oral option for ADT: you take a loading dose of three tablets on the first day, then one tablet daily after that. Being a daily pill rather than an injection gives patients more direct control over their treatment, and testosterone levels recover faster after stopping the drug.
GnRH antagonists also appear to carry a lower cardiovascular risk. A systematic review in JACC: CardioOncology found that major cardiovascular events occurred in 2.9% of patients on antagonists compared with 4.8% on agonists, translating to a 43% lower odds of heart attack, stroke, or death. This difference matters most for men who already have heart disease.
Androgen Receptor Inhibitors
Lowering testosterone is only part of the strategy. Even at castrate levels, small amounts of androgens can still fuel cancer growth. Androgen receptor inhibitors block the receptor itself, preventing any remaining androgens from activating it.
Older drugs in this class, like bicalutamide and flutamide, are called first-generation anti-androgens. They still see use for flare prevention, but they bind the androgen receptor weakly and can lose effectiveness as tumors adapt.
The second generation of these drugs is far more potent. Enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) bind the receptor with much greater strength and also prevent it from entering the cell nucleus, where it would otherwise switch on genes that drive tumor growth. In animal models, apalutamide shrank tumors in eight out of ten cases compared to just one out of ten with bicalutamide. Darolutamide has a distinct chemical structure from the other two, which appears to give it a lower rate of certain side effects like seizures and fatigue. All three are taken as daily pills, usually in combination with a GnRH agonist or antagonist.
CYP17 Inhibitors
Even after the testes are suppressed, the adrenal glands and sometimes the tumor itself can still produce small amounts of testosterone. Abiraterone acetate (Zytiga) blocks an enzyme called CYP17 that is essential for making androgens in these tissues. This makes it effective for cancers that continue to progress despite standard ADT.
Blocking CYP17 has a side effect: it disrupts the balance of other hormones made in the adrenal glands, which can cause high blood pressure, low potassium, and fluid retention. To counteract this, abiraterone is always taken alongside a low-dose corticosteroid like prednisone. You take it on an empty stomach, since food dramatically increases absorption and raises the risk of side effects.
How These Drugs Are Combined
In practice, ADT rarely means a single drug. The backbone of treatment is usually a GnRH agonist or antagonist to suppress testicular testosterone. For more aggressive or advanced cancers, a second-generation androgen receptor inhibitor or abiraterone is added on top. This “combined androgen blockade” attacks testosterone from multiple angles: stopping its production in the testes and adrenal glands while also blocking whatever traces remain from reaching the cancer.
The specific combination depends on whether the cancer is newly diagnosed, metastatic, or has become resistant to initial hormone therapy. Men with high-volume metastatic disease, for example, often start with a GnRH drug plus one of the newer agents from the outset, rather than waiting for the cancer to progress.
Continuous vs. Intermittent Schedules
Some men receive ADT continuously, while others follow an intermittent schedule designed to reduce side effects during “off” periods. In intermittent ADT, treatment is given for several months until PSA drops to a low level, then paused. If PSA rises again, typically to around 10 to 20 ng/mL depending on the protocol, treatment restarts. A large trial published in the New England Journal of Medicine tested this approach: after an initial treatment phase, men who achieved a PSA of 4.0 or lower were allowed to stop therapy until their PSA climbed back up.
Intermittent ADT can offer relief from hot flashes, fatigue, and sexual side effects during off cycles. It has not been shown to be clearly better or worse for survival in every setting, but it is generally considered a reasonable option for men without high-volume metastatic disease.
Side Effects Across Drug Classes
All forms of ADT share a common set of side effects driven by low testosterone: hot flashes, loss of libido, erectile dysfunction, fatigue, and loss of muscle mass. Bone loss is particularly significant. In the first year of ADT, men lose about 2.5% of bone density at the hip and up to 4% at the spine, with the fastest losses occurring early. This is why bone density monitoring and sometimes bone-protective medications are part of ADT management from the start.
Weight gain and metabolic changes are also common, with increased risk of diabetes and cardiovascular disease over time. The cardiovascular difference between GnRH agonists and antagonists noted above is one reason antagonists are increasingly preferred for men with preexisting heart conditions. Second-generation androgen receptor inhibitors add their own side effect profiles: enzalutamide can cause fatigue and, rarely, seizures; apalutamide is associated with skin rashes; darolutamide tends to have fewer central nervous system effects because less of it crosses into the brain.
Target Testosterone Levels
The traditional target for ADT is a testosterone level below 50 ng/dL, a threshold set decades ago based on the limits of older lab tests. Surgical castration actually lowers testosterone to around 20 ng/dL or less, and growing evidence suggests that achieving levels closer to this surgical benchmark may delay cancer progression. Some clinicians now aim for the lower threshold, though guidelines still use 50 ng/dL as the standard cutoff. If testosterone remains above that level despite medication, it signals that the current regimen needs adjustment.