Xtandi (enzalutamide) works by blocking testosterone from fueling prostate cancer cells at three distinct points in the signaling process. Most prostate cancers depend on male hormones called androgens to grow, and Xtandi is designed to shut down that hormonal signal more thoroughly than older treatments that only target one step. It’s taken as a daily oral pill for various stages of prostate cancer, from early biochemical recurrence to advanced metastatic disease.
Three Steps of Hormone Blocking
Prostate cancer cells have androgen receptors on their surface, essentially docking stations where testosterone and related hormones attach to trigger cell growth. Xtandi interferes with this process at three key stages, which is what sets it apart from older anti-androgen therapies.
First, it physically blocks androgens from binding to the receptor. Think of it as changing the lock so the key no longer fits. Second, even if the receptor does get activated, Xtandi prevents it from traveling into the cell’s nucleus, where it would normally switch on genes that tell the cancer to grow. Third, it stops the receptor from attaching to DNA inside the nucleus, which is the final step required for those growth signals to take effect. By hitting all three stages, Xtandi creates a more complete blockade of the hormonal pathway than drugs that only prevent the initial binding step.
What Xtandi Is Approved For
Xtandi is FDA-approved across a broad range of prostate cancer stages. It can be used for metastatic castration-resistant prostate cancer (where the disease has spread and no longer responds to standard hormone therapy), non-metastatic castration-resistant prostate cancer (where PSA levels are rising but no visible spread is detected on scans), and metastatic hormone-sensitive prostate cancer (where the disease has spread but still responds to hormone suppression).
More recently, the NCCN guidelines added support for using Xtandi in patients with biochemically recurrent prostate cancer, meaning their PSA levels are climbing after initial treatment like surgery or radiation, even without visible metastases. This applies specifically to patients at high risk of progression, defined as a PSA doubling time of nine months or less.
How Effective It Is
In the landmark AFFIRM trial, which studied men with metastatic castration-resistant prostate cancer who had already received chemotherapy, Xtandi extended median overall survival to 18.4 months compared to 13.6 months with placebo. That translates to a 37% reduction in the risk of death. Roughly half of patients saw their PSA levels drop by 50% or more within the first several months of treatment, with response rates holding steady between 49% and 52% at each four-week checkpoint through week 16.
How You Take It
The standard dose is 160 mg once daily, taken as either two 80 mg tablets or four 40 mg capsules. You can take it with or without food, which makes the daily routine fairly straightforward compared to some cancer medications that require specific timing around meals.
Common Side Effects
Fatigue is the most frequently reported side effect, affecting about 34% to 36% of patients across major clinical trials. Other common effects include hot flashes (18% to 20%), back pain (27% in one trial), diarrhea (21%), constipation (22%), musculoskeletal pain (14%), headache (12%), and hypertension (10% to 13%). Most of these are manageable, but the fatigue in particular can be significant enough to affect daily activities.
Seizures are a rare but serious risk. In eight randomized clinical trials, seizures occurred in 0.6% of patients taking Xtandi. That rate climbed to 2.2% in a study that specifically enrolled patients with predisposing factors like a history of brain injury, stroke, or use of medications that lower the seizure threshold.
Drug Interactions to Be Aware Of
Xtandi is a strong activator of a liver enzyme called CYP3A4, which the body uses to break down many common medications. This means Xtandi can cause other drugs to be processed faster than normal, reducing their effectiveness. Pain medications like oxycodone, fentanyl, methadone, and tramadol may need dose adjustments because Xtandi speeds up their metabolism. The same applies to blood thinners like dabigatran and immunosuppressants like tacrolimus and everolimus.
On the flip side, certain medications can affect how your body processes Xtandi itself. Strong inhibitors of CYP2C8, another liver enzyme, can cause Xtandi levels to build up. If a drug like that can’t be avoided, the Xtandi dose is typically reduced from 160 mg to 80 mg daily. This extensive web of interactions is one reason your oncology team will carefully review all your current medications before starting treatment.
Why Xtandi Can Stop Working
Over time, prostate cancer cells can develop resistance to Xtandi. The most well-studied escape route involves a shortened version of the androgen receptor called AR-V7. Normal androgen receptors have a binding pocket where Xtandi attaches to block the hormonal signal. AR-V7 is missing that pocket entirely, so Xtandi has nothing to latch onto. The receptor stays permanently active regardless of whether androgens or blocking drugs are present.
Cancer cells can also develop resistance through other routes: making extra copies of the androgen receptor gene, accumulating mutations that change the receptor’s shape, or switching to entirely different growth pathways that bypass androgen signaling altogether. In some cases, cancer cells transform into a neuroendocrine type that doesn’t rely on androgen receptors at all. When resistance develops, oncologists typically shift to a different treatment approach, such as chemotherapy or a different class of targeted therapy.