Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.

[2] Side effects of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and hot flashes.

[2] There is good evidence that enzalutamide is an effective treatment for increasing overall survival among people with high-risk non-metastatic castration-resistant prostate cancer, particularly those with a PSA doubling time ≤ 6 months.

[2] Notable side effects of enzalutamide seen in clinical trials have included gynecomastia, breast pain/tenderness, fatigue, diarrhea, hot flashes, headache, sexual dysfunction, and, less commonly, seizures.

[19][20][21][22] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).

[23] Enzalutamide monotherapy is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide.

[19][21] This is thought to be due to enzalutamide crossing the blood–brain barrier[25][26] and exerting off-target binding to and inhibition of the GABAA receptor in the central nervous system (it has been found to inhibit the GABAA receptor in vitro (IC50Tooltip half-maximal inhibitory concentration = 3.6 μM)[26][27][28] and induces convulsions in animals at high doses).

[19][21] In addition to seizures, other potentially GABAA receptor-related side effects observed with enzalutamide treatment in clinical trials have included anxiety, insomnia, vertigo, paresthesia, and headache.

[30] NSAA-induced seizures are responsive to benzodiazepine treatment, and it has been suggested that GABAA receptor inhibition by enzalutamide could be treated with these drugs.

[2] Enzalutamide is a moderate to strong inducer of multiple cytochrome P450 enzymes including CYP3A4, CYP2C9, and CYP2C19 and hence has a high potential for clinically relevant drug interactions.

[41] In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide.

[24][38] Also, unlike with the first-generation NSAAs, there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.

[56][57][58] They and their colleagues synthesized and evaluated nearly 200 thiohydantoin derivatives of RU-59063, an analogue of nilutamide, for AR antagonism in human prostate cancer cells, and identified enzalutamide and RD-162 as lead compounds.

[19][60] Enzalutamide was the first new AR antagonist to be approved for the treatment of prostate cancer in over 15 years, following the introduction of the first-generation NSAA bicalutamide in 1995.

[62] In December 2019, the FDA approved enzalutamide for the treatment of people with metastatic castration-sensitive prostate cancer (mCSPC).

[10] In June 2023, the FDA approved talazoparib, in combination with enzalutamide, for the treatment of people with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

[63] In November 2023, the FDA approved enzalutamide for the treatment of people with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis (high-risk BCR).