A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.
Medical uses NSAAs are used in clinical medicine for the following indications: Prostate cancer in men Androgen-dependent skin and hair conditions like acne, hirsutism, seborrhea, and pattern hair loss (androgenic alopecia) in women Hyperandrogenism, such as due to polycystic ovary syndrome or congenital adrenal hyperplasia, in women As a component of hormone therapy for transgender women Precocious puberty in boys Priapism in men
Available forms s marketed for clinical or veterinary use Generic name Class Type Brand name(s) Route(s) Launch Status Nonsteroidal Androgen synthesis inhibitor Cytadren, Orimeten Oral 1960 Availableb Nonsteroidal AR antagonist Erleada Oral 2018 Available Nonsteroidal AR antagonist Casodex Oral 1995 Available Nonsteroidal AR antagonist Xtandi Oral 2012 Available Nonsteroidal AR antagonist Eulexin Oral 1983 Available Nonsteroidal Androgen synthesis inhibitor and weak AR antagonist Nizoral, others Oral, topical 1981 Available Nonsteroidal AR antagonist Anandron, Nilandron Oral 1987 Available Nonsteroidal AR antagonist Eucapil Topical 2003 Availableb Footnotes: a = Hits = Google Search hits (as of February 2018). b = Availability limited / mostly discontinued. Class: Steroidal = . Nonsteroidal = . Sources: See individual articles.
Pharmacology Unlike SAAs, NSAAs have little or no capacity to activate the AR, show no off-target hormonal activity such as progestogenic, glucocorticoid, or antimineralocorticoid activity, and lack antigonadotropic effects. For these reasons, they have improved efficacy and selectivity as antiandrogens and do not lower androgen levels, instead acting solely by directly blocking the actions of androgens at the level of their biological target, the AR.
List of NSAAs
Marketed
First-generation Flutamide (Eulexin): Marketed for the treatment of prostate cancer and also used in the treatment of acne, hirsutism, and hyperandrogenism in women. It has also been studied in the treatment of benign prostatic hyperplasia. Now little-used due to high incidence of elevated liver enzymes and hepatotoxicity and the availability of safer agents. Nilutamide (Anandron, Nilandron): Marketed for the treatment of prostate cancer. Very little-used due to a high incidence of interstitial pneumonitis and high rates of several unique and unfavorable side effects such as nausea and vomiting, visual disturbances, and alcohol intolerance. Bicalutamide (Casodex): Marketed for the treatment of prostate cancer and also used in the treatment of hirsutism in women, as a component of hormone therapy for transgender women, to delay precocious puberty in boys, to prevent or alleviate priapism, and for other indications. It has also been studied in the treatment of benign prostatic hyperplasia. By far the most widely used NSAA, due to its favorable profile of efficacy, tolerability, and safety. Topilutamide (Eucapil): Also known as fluridil. Marketed as a topical medication for the treatment of pattern hair loss (androgenic alopecia) in the Czech Republic and Slovakia. Limited availability and lack of an oral formulation for systemic use make it a very little-known drug.
Second-generation Apalutamide (Erleada): Marketed for the treatment of prostate cancer. Very similar to enzalutamide, but with reduced central nervous system distribution and hence is expected to have a reduced risk of seizures and other central side effects. Enzalutamide (Xtandi): Marketed for the treatment of prostate cancer. More effective than the first-generation NSAAs due to increased efficacy and potency and shows no risk of elevated liver enzymes or hepatotoxicity. However, it has a small (1%) risk of seizures and has central nervous system side effects like anxiety and insomnia due to off-target inhibition of the GABAA receptor that the first-generation NSAAs do not have. In addition, it has prominent drug interactions due to moderate to strong induction of multiple cytochrome P450 enzymes. Currently on-patent with no generic availability and hence is very expensive. Darolutamide (Nubeqa): Marketed for the treatment of prostate cancer. Structurally distinct from enzalutamide, apalutamide, and other NSAAs. Relative to enzalutamide and apalutamide, shows greater efficacy as an AR antagonist, improved activity against mutated AR variants in prostate cancer, little or no inhibition or induction of cytochrome P450 enzymes, and little or no central nervous system distribution. However, has a much shorter terminal half-life and lower potency.
Miscellaneous Cimetidine (Tagamet): An over-the-counter histamine H2 receptor antagonist that also shows very weak activity as an AR antagonist. Also inhibits cytochrome P450 enzymes and thereby inhibits hepatic estradiol metabolism and increases circulating estradiol levels. It has been investigated in the treatment of hirsutism but showed minimal effectiveness. Sometimes causes gynecomastia as a rare side effect.
Nonsteroidal androgen synthesis inhibitors like ketoconazole can also be described as "NSAAs", although the term is usually reserved to describe AR antagonists.
Not marketed
Under development Proxalutamide (GT-0918): A second-generation NSAA. It is under development for the treatment of prostate cancer. Similar to enzalutamide and apalutamide, but with increased efficacy as an AR antagonist, little or no central nervous system distribution, and no induction of seizures in animals. Seviteronel (VT-464) is a nonsteroidal androgen biosynthesis inhibitor which is under development for the treatment of prostate cancer.
Development discontinued Cioteronel (CPC-10997; Cyoctol, Ethocyn, X-Andron): A structurally unique first-generation NSAA. It was under development as an oral medication for the treatment of benign prostatic hyperplasia and as a topical medication for the treatment of acne and pattern hair loss. It reached phase II and phase III clinical trials for these indications prior to discontinuation due to insufficient effectiveness. Inocoterone acetate (RU-38882, RU-882): A steroid-like NSAA. It was under development as a topical medication for the treatment of acne but was discontinued due to insufficient effectiveness in clinical trials. RU-58841 (PSK-3841, HMR-3841): A first-generation NSAA related to nilutamide. It was under development as a topical medication for the treatment of acne and pattern hair loss but its development was discontinued during phase I clinical trials.
See also Selective androgen receptor modulator N-Terminal domain antiandrogen Discovery and development of antiandrogens Nonsteroidal estrogen
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