Clinical data | |
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Trade names | Nubeqa |
Other names | Darramamide, ODM-201, BAY-1841788 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a619045 |
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Routes of administration | By mouth |
Drug class | Nonsteroidal antiandrogen |
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Pharmacokinetic data | |
Bioavailability | ≤30% [4] |
Protein binding | Darolutamide: 92% [4] Ketodarolutamide: 99.8% [4] |
Metabolism | Dehydrogenation (CYP3A4), glucuronidation (UGT1A9, UGT1A1) [4] |
Metabolites | Ketodarolutamide [4] [7] |
Elimination half-life | 16–20 hours [4] [7] |
Excretion | Urine: 63.4% [4] Feces: 32.4% [4] |
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ChEMBL | |
ECHA InfoCard | 100.264.885 |
Chemical and physical data | |
Formula | C19H19ClN6O2 |
Molar mass | 398.85 g·mol−1 |
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Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. [8] [4] [5] [9] [10] It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. [4] The medication is taken by mouth twice per day with food. [4]
Side effects of darolutamide added to castration may include fatigue, asthenia, pain in the arms and legs, and rash. [4] Darolutamide is a nonsteroidal antiandrogen (NSAA), and acts as a selective antagonist of the androgen receptor (AR). [4] [9] [10] It has been referred to as a second- or third-generation NSAA. [11] [12]
Darolutamide was patented in 2011 [13] and was approved for medical use in USA in July 2019, [8] [14] in the European Union in March 2020 [5] in Australia in July 2020. [15] and in Canada in 2020,
Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone (GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) in men. [9] [10] It is used at a dosage of 600 mg orally twice per day (1,200 mg/day total) with food. [4] In individuals with severe renal impairment or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food. [4] No dosage adjustment is needed for mild to moderate renal impairment or mild hepatic impairment, whereas appropriate dosage adjustment for end-stage kidney disease and severe hepatic impairment is unknown. [4]
Two 2020 meta-analyses reported that enzalutamide and apalutamide seemed to be more effective than darolutamide in improving metastasis-free survival (MFS), however 2021 matched adjusted indirect comparison showed no significant differences between drugs in terms of MFS. [16] [17] [18] According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS). [19] Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide. [19]
Darolutamide is provided in the form of 300 mg oral film-coated tablets. [4]
Darolutamide has no contraindications in men. [4] However, the medication may have teratogenic effects in male fetuses due to its antiandrogenic effects and hence should not be used by women who are pregnant. [4]
The most common side effects of darolutamide in clinical trials (≥2% incidence) in castrated men included fatigue and asthenia (16% vs. 11% for placebo), pain in extremities (6% vs. 3% for placebo), and rash (3% vs. 1% for placebo). [4] Darolutamide was also associated with higher incidences of ischemic heart disease (4.0% vs. 3.4% for placebo) and heart failure (2.1% vs. 0.9% for placebo). [4] In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased aspartate aminotransferase (AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased bilirubin (16% vs. 7% for placebo). [4] In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older. [4]
No seizures have been observed with darolutamide in clinical trials. [7] [20] Darolutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy. [4] It may impair male fertility. [4] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia. [21]
Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. [4] There were no dose-limiting toxicities seen at this dosage. [4] Due to its saturable absorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function. [4] There is no specific antidote for overdose of darolutamide. [4] In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. [4] If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued. [4]
Combined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase blood levels of darolutamide. [4] Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase blood levels of substrates for BCRP protein, such as rosuvastatin, by approximately 5-fold. [4]
Darolutamide is a second- or third-generation nonsteroidal antiandrogen (NSAA). [11] [12] It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). [4] Its affinity (Ki) for the AR is 11 nM and its functional inhibition (IC50 Tooltip half-maximal inhibitory concentration) of the AR is 26 nM. [10] The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8 nM; IC50 = 38 nM). [4] [10] In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the progesterone receptor (PR), with approximately 1% of the potency of its AR antagonism. [4]
A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in prostate specific antigen (PSA) levels of more than 90% in men with prostate cancer. [4] [ additional citation(s) needed ] The addition of darolutamide to castration has been found to decrease PSA levels by more than 50% in about 50% of men at 200 mg/day, 69% of men at 400 mg/day, 83% of men at 1,200 mg/day, and 86% of men at 1,400 mg/day. [22] [10] [7]
Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs. [10] It appears to negligibly cross the blood–brain barrier, and hence has reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition. [10] In accordance with its diminished central penetration, darolutamide does not appear to increase testosterone levels. [10] Darolutamide has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance to enzalutamide and apalutamide. [10] The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide in vitro (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; IC50 Tooltip half-maximal inhibitory concentration = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide). [10]
Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters OATP1B1 and OATP1B3 in vitro. [4] It shows no inhibition or induction of cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. [23] Similarly, darolutamide shows no inhibition of a variety of other transporters (P-glycoprotein, MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, NTCP) at therapeutic concentrations. [4] [24]
The absolute bioavailability of darolutamide with oral administration of a single 300-mg dose without food is approximately 30%. [4] The bioavailability of darolutamide is increased by about 2- to 2.5-fold when administered with food, with a similar increase in exposure occurring for ketodarolutamide. [4] Exposure to darolutamide and ketodarolutamide increases in a nearly linear or dose-proportional manner across a dose range of 100 to 700 mg (or about 0.17- to 1.17-fold the recommended 600-mg dosage). [4] No further increase in exposure to darolutamide was observed at a dosage of darolutamide of 900 mg twice per day (or 1.5 times the recommended 600-mg dosage), indicating a saturation of absorption at doses above 700 mg. [4] Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. [4] Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs. [4] At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC0–12) are 52.82 h•μg/mL. [4] Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide. [4]
The volume of distribution of darolutamide with intravenous administration is 119 L. [4] The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. [4] As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. [4] Both darolutamide and ketodarolutamide are bound mainly to albumin. [4] Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans. [10] Darolutamide is a known substrate of P-glycoprotein and the breast cancer resistance protein (BCRP). [25] [26] [27] P-Glycoprotein is known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier. [28] [29]
Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver. [4] The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1. [4] The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours. [4] A clinical study found that the elimination half-lives of darolutamide and ketodarolutamide at steady-state were 15.8 hours and 10.0 hours, respectively, with these half-lives being independent of dosage across a dose range of darolutamide of 200 to 1,800 mg/day. [7] The elimination half-life of darolutamide is far shorter than that of enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice). [10] The clearance of darolutamide following intravenous administration is 116 mL/min. [4]
After a single oral dose of darolutamide, more than 95% of the dose is excreted in urine and feces within one week following administration. [4] A total of 63.4% darolutamide-related material is recovered in urine (about 7% as unchanged darolutamide) and a total of 32.4% darolutamide-related material (about 30% as unchanged darolutamide) is recovered in feces. [4]
No clinically significant differences in the pharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate renal impairment, or mild hepatic impairment. [4] In non-nmCRPC individuals with severe renal impairment not on dialysis, exposure to darolutamide was increased by about 2.5-fold relative to healthy people. [4] In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. [4] The pharmacokinetics of darolutamide have not been assessed in end-stage kidney disease or severe hepatic impairment. [4]
Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide. [10]
Darolutamide was developed by Orion Corporation and Bayer HealthCare. [30] Orion Corporation applied for a patent on darolutamide in October 2010, and this patent was published in May 2011. [13] Darolutamide entered phase I clinical trials in April 2011, [31] with the results of the first clinical study of darolutamide initially published in 2012. [32] The U.S. Food and Drug Administration (FDA) approved darolutamide in July 2019, under the agency's priority review designation. [8]
Approval was based on ARAMIS, [33] a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm. [8] [14]
The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001).
Darolutamide was associated with greater benefits than placebo for all secondary end points, including overall survival (hazard ratio 0.69; 95% CI: 0.53-0.88; P=0.003), time to pain progression (median 40.3 months vs. 25.4 months; hazard ratio 0.65; 95% CI: 0.53-0.79; P<0.001), time to cytotoxic chemotherapy (hazard ratio 0.43; 95% CI: 0.31-0.60), and time to a symptomatic skeletal event (hazard ratio 0.43; 95% CI: 0.22-0.84). [33]
Darolutamide is the generic name of the medication and its INN Tooltip International Nonproprietary Name and USAN Tooltip United States Adopted Name. [34] It is also known by its developmental code names ODM-201 and BAY-1841788. [30]
Darolutamide is marketed under the brand name Nubeqa. [4] [8] [5]
Darolutamide is available in the United States and the European Union. [4] [8] [5] [35]
Darolutamide monotherapy is being studied in comparison to androgen deprivation therapy with GnRH agonist or antagonist monotherapy in men with treatment-naive prostate cancer. [22] [36] As of 2018, it is entering a phase II clinical trial for this indication. [22] [36] This study is expected for completion in 2021 or 2022. [37]
Darolutamide is being studied for the treatment of breast cancer in women. [30] As of November 2019, it is in phase II clinical trials for this indication. [30]
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.
Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC). It should either be used following removal of the testicles or along with a gonadotropin-releasing hormone (GnRH) analog. It is taken by mouth.
Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.
Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.
Galeterone is a steroidal antiandrogen which was under development by Tokai Pharmaceuticals for the treatment of prostate cancer. It possesses a unique triple mechanism of action, acting as an androgen receptor antagonist, androgen receptor down regulator, and CYP17A1 inhibitor, the latter of which prevents the biosynthesis of androgens. As a CYP17A1 inhibitor, galeterone shows selectivity for 17,20-lyase over 17α-hydroxylase.
Tasquinimod is an experimental drug currently being investigated for the treatment of solid tumors. Tasquinimod has been mostly studied in prostate cancer, but its mechanism of action suggests that it could be used to treat other cancers. Castration-resistant prostate cancer (CRPC), formerly called hormone-resistant or hormone-refractory prostate cancer, is prostate cancer that grows despite medical or surgical androgen deprivation therapy. Tasquinimod targets the tumor microenvironment and counteracts cancer development by inhibiting angiogenesis and metastasis and by modulating the immune system. It is now in phase III development, following successful phase II trial outcomes.
PROSTVAC is a cancer immunotherapy candidate in clinical development by Bavarian Nordic for the treatment of all prostate cancer although clinical trials are focusing on more advanced cases of metastatic castration-resistant prostate cancer (mCRPC). PROSTVAC is a vaccine designed to enable the immune system to recognize and attack prostate cancer cells by triggering a specific and targeted T cell immune response to cancer cells that express the tumor-associated antigen prostate-specific antigen (PSA).
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.
Seviteronel is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer. It is a nonsteroidal CYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body. As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer. In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer. In April 2017, seviteronel received fast-track designation for breast cancer as well.
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth.
Ralaniten acetate is a first-in-class antiandrogen that targets the N-terminal domain (NTD) of the androgen receptor (AR) developed by ESSA Pharmaceuticals and was under investigation for the treatment of prostate cancer. This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants. EPI-506 is a derivative of bisphenol A and a prodrug of ralaniten (EPI-002), one of the four stereoisomers of EPI-001, and was developed as a successor of EPI-001. The drug reached phase I/II prior to the discontinuation of its development. It showed signs of efficacy in the form of prostatic specific antigen (PSA) decreases (4–29%) predominantly at higher doses (≥1,280 mg) in some patients but also caused side effects and was discontinued by its developer in favor of next-generation AR NTD inhibitors with improved potency and tolerability.
Proxalutamide is a nonsteroidal antiandrogen (NSAA) – specifically, a selective high-affinity silent antagonist of the androgen receptor (AR) – which is under development by Suzhou Kintor Pharmaceuticals, inc., a subsidiary of Kintor Pharmaceutical Limited, for the potential treatment of COVID-19, prostate cancer, and breast cancer. It was approved in Paraguay for the treatment of COVID-19 in July 2021, but has not been approved at this time in other countries.
Ketodarolutamide is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of darolutamide, an NSAA which is used in the treatment of prostate cancer in men. Similarly to its parent compound, ketodarolutamide acts as a highly selective, high-affinity, competitive silent antagonist of the androgen receptor (AR). Both agents show much higher affinity and more potent inhibition of the AR relative to the other NSAAs enzalutamide and apalutamide, although they also possess much shorter and comparatively less favorable elimination half-lives. They have also been found not to activate certain mutant AR variants that enzalutamide and apalutamide do activate. Both darolutamide and ketodarolutamide show limited central nervous system distribution, indicating peripheral selectivity, and little or no inhibition or induction of cytochrome P450 enzymes such as CYP3A4, unlike enzalutamide and apalutamide.
N-Desmethylenzalutamide is a nonsteroidal antiandrogen (NSAA) and the major metabolite of enzalutamide, an NSAA which is used as a hormonal antineoplastic agent in the treatment of metastatic prostate cancer. It has similar activity to that of enzalutamide and, with enzalutamide therapy, circulates at similar concentrations to those of enzalutamide at steady state. N-Desmethylenzalutamide is formed from enzalutamide in the liver by the cytochrome P450 enzymes CYP2C8 and CYP3A4. It has a longer terminal half-life than enzalutamide.
The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
RD-162 is a second-generation nonsteroidal antiandrogen (NSAA) which was developed for the treatment of prostate cancer but was never marketed. It acts as a potent and selective silent antagonist of the androgen receptor (AR). The drug is a diarylthiohydantoin derivative. It is closely related to enzalutamide and apalutamide. Both RD-162 and enzalutamide show 5- to 8-fold higher affinity for the AR than the first-generation NSAA bicalutamide, and only 2- to 3-fold lower affinity than dihydrotestosterone (DHT), the major endogenous ligand of the receptor in the prostate gland.
Rezvilutamide, sold under the brand name Ariane, is a nonsteroidal antiandrogen which is approved for the treatment of prostate cancer in China and is or was under development for the treatment of breast cancer. It is a selective androgen receptor antagonist with reduced brain distribution compared to the structurally related nonsteroidal antiandrogen enzalutamide. The drug was developed by Jiangsu Hengrui Medicine. Other structural analogues of rezvilutamide that are also used as antiandrogens besides enzalutamide include apalutamide and proxalutamide.