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Darolutamide, a New Second-Generation Nonsteroidal Antiandrogen, Has Been Approved for Medical Use

By Aly W. | First published September 3, 2019 | Last modified October 5, 2020

Darolutamide (brand name Nubeqa), a new second-generation nonsteroidal antiandrogen, was just approved for medical use by the FDA in the United States. It was specifically approved for the treatment of prostate cancer in men, similarly to bicalutamide. This is the first global approval of darolutamide as a medication.

You can read more about darolutamide at the following links:

Darolutamide is a second-generation nonsteroidal antiandrogen and hence is a highly efficacious and selective antagonist of the androgen receptor, the main biological target of androgens like testosterone and dihydrotestosterone in the body. Darolutamide and other second-generation nonsteroidal antiandrogens like enzalutamide and apalutamide are notable in that they have much higher affinity for the androgen receptor and greater antiandrogenic efficacy than first-generation nonsteroidal antiandrogens like bicalutamide, flutamide, and nilutamide. The affinities of these antiandrogens for the androgen receptor are about 5- to 10-fold higher than that of bicalutamide. Although clinical potency is more complex than just affinity, the second-generation nonsteroidal antiandrogens indeed seem to be considerably more capable as antiandrogens than bicalutamide and the other first-generation nonsteroidal antiandrogens. Shortly following the introduction of enzalutamide in 2012, it was amusingly referred to as the “emperor of all antiandrogens” in the title of one review publication (Antonarakis, 2013).

Enzalutamide and apalutamide have certain unfavorable properties however due to non-selectivity for the androgen receptor. Specifically, they are strong inducers of cytochrome P450 enzymes such as CYP3A4, which notably metabolize estradiol and other medications used in transfeminine hormone therapy. In addition, enzalutamide and apalutamide are weak negative allosteric modulators of the GABAA receptor, and hence have a risk of seizures and other off-target central-nervous-system adverse effects such as anxiety and insomnia. These properties are undesirable and limit the appeal of these two new antiandrogens in transgender women.

Darolutamide has none of the problems of enzalutamide and apalutamide. It does not induce nor inhibit any major cytochrome P450 enzymes at clinically relevant concentrations, and hence has a much better profile when it comes to drug interactions. In addition, darolutamide appears to negligibly cross the blood–brain barrier. As a result, it has no risk of off-target central-nervous-system side effects, including seizures.

Darolutamide does unfortunately have some issues of its own however. One issue is that whereas bicalutamide, enzalutamide, and apalutamide all have long half-lives (e.g., 3 to 10 days), darolutamide has a relatively short half-life of only about 16 to 20 hours. As a result, it needs to be taken twice per day at roughly 12-hour intervals, similarly to spironolactone. Another issue is that, similarly to first-generation nonsteroidal antiandrogens like flutamide, nilutamide, and bicalutamide, darolutamide has been associated with abnormal liver function tests (specifically elevated AST levels and increased bilirubin levels). This is unfortunate, as it indicates that darolutamide may pose a small risk of liver toxicity similarly to bicalutamide. In contrast, enzalutamide and apalutamide are not associated with abnormal liver function tests. In any case, with its lack of seizures and major drug interactions, the profile of darolutamide is arguably nonetheless still greatly advantageous to that of enzalutamide and apalutamide.

One unique and very special property of darolutamide is that the medication, as mentioned above, appears to negligibly cross the blood–brain barrier. This is based on the fact that androgen-receptor antagonists consistently increase testosterone levels by up to about 2-fold due to blockade of the androgen receptor in the pituitary gland, whereas darolutamide does not affect testosterone levels. The lack of blockade of the androgen receptor in the brain with darolutamide is notable for the following reasons:

  • In transfeminine non-binary individuals who do not want to block the effects of androgens in the brain, for instance to fully preserve sexual desire and function, darolutamide can potentially allow for this.
  • Due to the absence of increase in testosterone levels with darolutamide, the medication may allow for more effective and less complicated antiandrogen monotherapy in transgender women as well as transfeminine non-binary individuals and femboys. This may be particularly true when combining it with selective estrogen receptor modulators like raloxifene, which increase testosterone levels themselves (Aly W., 2019).

At the same time however, the lack of blood–brain barrier permeation with darolutamide can obviously also be a drawback. If darolutamide does not cross into the brain, then it will not block androgen signaling in the brain and will not prevent the masculinizing effects of androgens on cognition, emotionality, sexuality, and so forth. With that said however, estrogens and progestogens suppress testosterone levels, and can hence substantially diminish the brain effects of androgens in the body regardless of whether darolutamide is the antiandrogen or enters the brain. In this context, the lack of brain penetration of darolutamide may not be as significant of an issue for transgender women.

One final and very important general caveat of the second-generation nonsteroidal antiandrogens is that they all still have patent protection, and hence are very expensive (e.g., $6,000 for one month of treatment). And insurance almost certainly will not approve coverage of them for use in transgender hormone therapy. Moreover, these medications will be remaining on-patent for many more years. Enzalutamide was introduced in 2012, while apalutamide was approved in 2018 and darolutamide was of course just licensed now in 2019. Patent protection on medications generally lasts around 10 to 15 years. Only once patent protection expires will inexpensive generic versions be marketed and will we see darolutamide and the other second-generation nonsteroidal antiandrogens become affordable.

That day will eventually come though, and when it does, I think that darolutamide and the other second-generation nonsteroidal antiandrogens, along with orally active GnRH antagonists like elagolix and relugolix (Aly W., 2018; Aly W., 2019), will be fantastic additions to the available medication options for transfeminine hormone therapy.