Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[9][10] It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC),[9] nonmetastatic castration-resistant prostate cancer,[9] and metastatic castration-sensitive prostate cancer (mCSPC).[11] It is taken by mouth.[9]
Side effects of enzalutamide when added to castration include asthenia, back pain, diarrhea, arthralgia, and hot flashes.[9] Rarely, it can cause seizures.[9] It has a high potential for drug interactions.[9] Enzalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[9] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.[9]
Enzalutamide was first described in 2006, and was introduced for the treatment of prostate cancer in 2012.[12][13] It was the first second-generation NSAA to be introduced. Enzalutamide is a therapeutic alternative on the World Health Organization's List of Essential Medicines.[14]
Medical uses
Enzalutamide is indicated for the treatment of people with castration-resistant prostate cancer; metastatic castration-sensitive prostate cancer; and non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis.[9]
Prostate cancer
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.[15]
Other uses
Enzalutamide can be used as an antiandrogen in feminizing hormone therapy for transgender women.[16][17]
Contraindications
Enzalutamide is contraindicated in women during pregnancy.[9] It may cause fetal harm.[9]
Side effects
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.[18][19][20] Other "common" side effects reported in clinical trials have included neutropenia, visual hallucinations, anxiety, cognitive disorder, memory impairment, hypertension, dry skin, and pruritus (itching).[21] 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.
Overdose
Enzalutamide may cause seizures in overdose.[9]
Interactions
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.[9] Circulating concentrations of enzalutamide may be altered by inhibitors and inducers of CYP2C8 and CYP3A4, and should be avoided if possible.
In a clinical study of enzalutamide for ER-positive breast cancer in women, enzalutamide was found to decrease serum concentrations of the aromatase inhibitors anastrozole and exemestane by 90% and 50%, respectively, which could reduce their effectiveness.[30]
Pharmacology
Pharmacodynamics
Enzalutamide acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Unlike the first-generation NSAA bicalutamide, enzalutamide does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins. As such, it has been described as an AR signaling inhibitor in addition to antagonist.[31] The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2-fold lower affinity for the AR than DHT, the endogenous ligand of the AR in the prostate gland.[32]
When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with enzalutamide, the expression of androgen-dependent genes PSA and
Chemistry
Enzalutamide is a synthetic diaryl thiohydantoin derivative and is structurally related to the earlier first-generation NSAAs such as flutamide, nilutamide, and bicalutamide as well as to newer second-generation NSAAs like apalutamide and proxalutamide.[54]
History
Enzalutamide was discovered by Charles Sawyers and Michael Jung at the University of California, Los Angeles.[55][56][57] 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.[36][57] These compounds were patented in 2006 and described in 2007.[58]
Society and culture
Legal status
In June 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Enzalutamide Viatris, intended for the treatment of prostate cancer.[66] The applicant for this medicinal product is Viatris Limited.[67] Enzalutamide Viatris is a generic of Xtandi.[67]
Economics
Pfizer reported revenue of US$1.191 billion for Xtandi in 2023.[68]
Research
Breast cancer
Research suggests that enzalutamide may be effective in the treatment of certain types of breast cancer in women.[69][70] It has been tested for the treatment of triple-negative, AR-positive breast cancer in a phase II clinical trial.[71][72]
Hirsutism
Enzalutamide has been suggested as a potential treatment for hirsutism and hyperandrogenism in women with polycystic ovary syndrome.[73]
See also
- Mevrometostat
References
- Enzalutamide (Xtandi) Use During Pregnancy Drugs.com, 4 September 2018, retrieved 21 December 2019^
- Prescription medicines: registration of new chemical entities in Australia, 2014 Therapeutic Goods Administration (TGA), 21 June 2022, retrieved 10 April 2023^
- Xtandi (Astellas Pharma Australia Pty Ltd)