Newly identified adverse events of enzalutamide using the food and drug administration adverse event reporting system

ABSTRACT

Objectives

Enzalutamide, a second-generation anti-androgen drug, is an androgen receptor inhibitor developed to overcome resistance to first-generation anti-androgens, such as bicalutamide. This study aimed to identify previously undisclosed adverse events associated with enzalutamide.

Methods

Adverse reactions following enzalutamide administration were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, and the data obtained were from 2014 to 2023. Four algorithms, namely ROR, PRR, BCPNN, and EBGM, were used to detect signs of adverse reactions associated with enzalutamide use.

Results

This study determined several adverse reactions in the nervous system, including hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorders, and seizure-like phenomena. The mental aspects manifested as laziness, confusion, and eating disorders. Gastrointestinal system-related adverse reactions included dysphagia, constipation, fecal hardening, and abdominal discomfort. We identified several previously unreported adverse reactions, including normal-pressure hydrocephalus, dementia, balance disorders, eating disorders, and dysphagia.

Conclusion

Our study revealed novel adverse events associated with enzalutamide, particularly in the nervous system, that have not been previously documented. These findings have important implications for future clinical medication guidelines.

KEYWORDS:

• Enzalutamide
• FAERS
• adverse event
• mCRPC
• nervous system

1. Introduction

Androgen receptor (AR), a nuclear hormone receptor, can be activated by various ligands, including dihydrotestosterone, leading to its nuclear localization and subsequent transcription of target genes [1]. Enzalutamide, a second-generation anti-androgen drug, is an AR inhibitor developed to address resistance to first-generation anti-androgens [2]. In combination with AR, enzalutamide prevents nuclear translocation, thereby inhibiting interactions between AR and DNA [3].

Enzalutamide demonstrates superior progression-free survival compared with the first-generation anti-androgenic drug bicalutamide in treating metastatic castration-resistant prostate cancer (mCRPC) [4]. Its favorable survival benefits and safety profile led to its approval for mCRPC treatment in 2012 [5–7].

Furthermore, the FDA Adverse Event Reporting System (FAERS) is a database established to facilitate the FDA’s post-marketing monitoring program for drugs and biological therapeutic products, and contains information on the AEs and medication errors reported by the FDA. However, the FAERS has certain limitations. First, the reporting of events did not establish a causal relationship between the AEs and the implicated drug. Secondly, the database may not have captured all adverse event reports or medication errors associated with a particular drug. However, data mining techniques can yield valuable insights from this database, offering a reference for analyzing adverse reactions to enzalutamide. Yang et al. used the FAERS database to identify the development of eye disorders in patients treated with topotecan [8], while another study revealed an association between fluoroquinolone use, tendonitis, and tendon rupture [9].

This study aimed to extract information on adverse reactions following enzalutamide treatment from the FAERS database using data mining technology, explore the actual adverse reactions to enzalutamide in real-world scenarios, and conduct relevant analyses to determine its incident rates.

2. Materials and methods

2.1. Data acquisition and processing

First, information on adverse reactions following enzalutamide use was obtained from the FAERS database (https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysis) from 2014 to 2023. Next, the data for each quarter were consolidated and preprocessed using MySQL and SAS software. Data cleaning was then performed based on official documentation, which involved selecting the latest FDA_DT when the CASEID was the same, and the higher PRIMARYID when both CASEID and FDA_DT were the same. Finally, each adverse reaction record was mapped to the corresponding System Organ Class (SOC) levels and preferred Terms (PTs).

2.2. Statistical analysis

Four algorithms – ROR, PRR, BCPNN, and EBGM – were employed to detect the signals of adverse reactions following the use of enzalutamide. The formulas and positive safety signal thresholds for each algorithm are listed in Supplementary Table S1. Adverse reactions identified as positive signals using all four algorithms were retained to enhance the reliability of the results. To investigate whether the adverse events we found differed among age subgroups, we performed subgroup analyzes. Three different statistical methods were used to compare the distribution of adverse events between the age subgroups: chi-square test, chi-square continuity correction, and Fisher’s exact probability test. These methods efficiently assessed the differences between different age subgroups in different data contexts. P < 0.05 was considered statistically significant.

3. Results

3.1. Characteristics of the data

Between 2014 and 2023, 13703,053 reports were obtained from the FAERS database. After the data-cleaning process, 11878,558 reports remained. Among these reports, 40238 individuals experienced 118,103 adverse reactions following enzalutamide administration. Table 1 presents the clinical features of adverse reactions associated with enzalutamide. Among the patients, 98.09% were men, and 0.59% were women. The reason for women using enzalutamide in the database was almost exclusively accidental exposure to the product. Patients aged <60 years accounted for 8.5%, whereas those >60 years were 48.5%. The most frequent adverse reaction outcome was classified as ‘other serious,’ followed by death and hospitalization. The top three countries that reported adverse reactions were the U.S.A. (82.84%), Japan (5.51%), and the United Kingdom (1.02%). Adverse reactions were primarily reported by consumers (71.68%), physicians (12.56%), healthcare professionals (10.55%), and pharmacists (3.69%). The year with the highest number of adverse reactions reported over the past decade was 2017.

Table 1. The characters of case reports associated with enzalutamide.

	count	Percentage
Number of events	40238
Gender
Female	239	.594
Male	39468	98.0864
Unknow	531	1.3196
Age (year)
≤65	3410	8.5
>65	19507	48.5
Unknown	17321	43
Serious outcome
Other serious(OT)	8958	22.2625
Death (DE)	8761	21.7729
Hospitalization(HO)	5445	13.532
Unknown	17119	42.4326
Reporting region
US	33334	82.8421
JP	2216	5.5072
GB	410	1.0189
Others	4278	1.6318
Reported person
Consumer(CN)	28842	71.6785
Physician (MD)	5055	12.5628
Other health professional(OT)	4245	1.5497
Pharmacist (PH)	1485	3.6905
Others	611	1.5185
Reporting year
2014	2422	6.0192
2015	4962	12.3316
2016	6668	16.5714
2017	9648	23.9773
2018	7684	19.0964
2019	3201	7.9552
2020	2069	5.1419
2021	1773	4.4063
2022	1488	3.698
2023	323	.8027

3.2. Signal detects at SOC and PTs Level

All adverse reaction records that exhibited positive signals in the four algorithms were included in Supplementary Table S2, encompassing 84 PTs distributed among the 10 SOC. This study specifically focused on drug reactions within the neurological, gastrointestinal, and psychiatric categories of interest (Table 2). Enzalutamide administration elicits several noteworthy effects on the nervous system. Hypogeusia (Case number: 21; ROR: 5.85 [3.8–9.01]; PRR: 5.85 [3.8–9.01]; IC: 2.52[1.62–2.86]; EBGM: 5.75 [3.73–8.86]), ageusia (Case number: 185; ROR: 4.17 [3.61–4.83]; PRR: 4.17 [3.61–4.82]; IC: 2.04 [1.81–2.23]; EBGM: 4.12 [3.57–4.77]), and dysgeusia (Case number: 475; ROR: 3.47 [3.17–3.8]; PRR: 3.46 [3.17–3.79]; IC: 1.78[1.64–1.91]; EBGM: 3.44 [3.14–3.76]) were observed as potential adverse effects. Additionally, enzalutamide usage was associated with occurrences of normal pressure hydrocephalus (Case number:5; ROR:7.53[3.1–18.29]; PRR:7.53[3.1–18.29]; IC:2.88[0.64–3.03]; EBGM:7.36 [3.03–17.89]), dementia (Case number:182; ROR:3.5 [3.03–4.06]; PRR:3.5 [3.03–4.05]; IC:1.8 [1.56–1.99]; EBGM:3.47 [3–4.02]), amnesia (Case number:365; ROR:3.26 [2.94–3.61]; PRR:3.25 [2.93–3.6]; IC:1.69 [1.53–1.83]; EBGM:3.22 [2.91–3.58]), and balance disorder (Case number:466; ROR:2.84[2.59–3.11]; PRR:2.83[2.59–3.1]; IC:1.49 [1.35–1.62]; EBGM:2.81 [2.57–3.08]). Furthermore, enzalutamide treatment was associated with adverse effects on the mental aspect, including laziness (Case number:23; ROR:6.41[4.24–9.68]; PRR:6.4[4.24–9.68]; IC:2.65 [1.77–2.96]; EBGM:6.29 [4.16–9.51]), confusing state (Case number:676; ROR:2.32[2.15–2.5]; PRR:2.31[2.14–2.49]; IC:1.2 [1.09–1.31]; EBGM:2.3 [2.13–2.48]), and eating disorder (Case number:111; ROR:2.58[2.14–3.11]; PRR:2.58[2.14–3.11]; IC:1.36 [1.06–1.61]; EBGM:2.56 [2.13–3.09]). Moreover, gastrointestinal manifestations such as dysphagia (Case number:1063; ROR:6.39[6.01–6.79]; PRR:6.34[5.97–6.74]; IC:2.64 [2.54–2.72]; EBGM:6.23 [5.86–6.62]) and constipation (Case number:1295; ROR:3.19[3.02–3.37]; PRR:3.17[3–3.34]; IC:1.65 [1.57–1.73]; EBGM:3.14 [2.98–3.32]) were observed. Additionally, occurrences of hard feces (Case number:28; ROR:3.83[2.64–5.57]; PRR:3.83[2.64–5.57]; IC:1.92 [1.25–2.33]; EBGM:3.8[2.62–5.51]) and abdominal discomfort (Case number:751; ROR:2.18[2.03–2.34]; PRR:2.17[2.02–2.33]; IC:1.11 [1–1.22]; EBGM:2.16 [2.01–2.32]) were reported within the gastrointestinal system.

Table 2. The signal strength of AEs of enzalutamide at the SOC and PTs level in the FAERS database.

SOC Name	PTs	SOC Code	Case Numbers	ROR (95% CI)	PRR (95% CI)	Chi square	IC (95% CI)	EBGM (95% CI)
Nervous system disorders	Restless legs syndrome	10029205	151	4.51 (3.84–5.3)	4.51 (3.84–5.29)	405.8184	2.15 (1.89–2.36)	4.45 (3.79–5.23)
	Hypogeusia	10029205	21	5.85 (3.8–9.01)	5.85 (3.8–9.01)	82.72857	2.52 (1.62–2.86)	5.75 (3.73–8.86)
	Spinal cord compression	10029205	38	5.13 (3.73–7.08)	5.13 (3.72–7.07)	124.2529	2.34 (1.73–2.66)	5.06 (3.67–6.97)
	Ageusia	10029205	185	4.17 (3.61–4.83)	4.17 (3.61–4.82)	439.3094	2.04 (1.81–2.23)	4.12 (3.57–4.77)
	Dysgeusia	10029205	475	3.47 (3.17–3.8)	3.46 (3.17–3.79)	823.8647	1.78 (1.64–1.91)	3.44 (3.14–3.76)
	Normal pressure hydrocephalus	10029205	5	7.53 (3.1–18.29)	7.53 (3.1–18.29)	27.58406	2.88 (0.64–3.03)	7.36 (3.03–17.89)
	Hypersomnia	10029205	189	3.5 (3.03–4.04)	3.49 (3.03–4.03)	332.5195	1.79 (1.56–1.98)	3.46 (3–4)
	Dementia	10029205	182	3.5 (3.03–4.06)	3.5 (3.03–4.05)	321.3737	1.8 (1.56–1.99)	3.47 (3–4.02)
	Amnesia	10029205	365	3.26 (2.94–3.61)	3.25 (2.93–3.6)	562.6343	1.69 (1.53–1.83)	3.22 (2.91–3.58)
	Balance disorder	10029205	466	2.84 (2.59–3.11)	2.83 (2.59–3.1)	547.7954	1.49 (1.35–1.62)	2.81 (2.57–3.08)
	Dizziness	10029205	2220	2.41 (2.31–2.51)	2.38 (2.28–2.48)	1775.357	1.24 (1.18–1.31)	2.37 (2.27–2.47)
	Seizure like phenomena	10029205	13	3.72 (2.16–6.44)	3.72 (2.16–6.44)	25.57725	1.88 (0.85–2.41)	3.69 (2.13–6.38)
Psychiatric disorders	Laziness	10037175	23	6.41 (4.24–9.68)	6.4 (4.24–9.68)	102.6348	2.65 (1.77–2.96)	6.29 (4.16–9.51)
	Initial insomnia	10037175	54	3.48 (2.66–4.55)	3.48 (2.66–4.55)	94.29229	1.79 (1.33–2.11)	3.45 (2.64–4.51)
	Confusional state	10037175	676	2.32 (2.15–2.5)	2.31 (2.14–2.49)	499.6215	1.2 (1.09–1.31)	2.3 (2.13–2.48)
	Eating disorder	10037175	111	2.58 (2.14–3.11)	2.58 (2.14–3.11)	106.3241	1.36 (1.06–1.61)	2.56 (2.13–3.09)
Gastrointestinal disorders	Malignant dysphagia	10017947	3	32.12 (9.74–105.88)	32.12 (9.74–105.87)	81.40212	4.86 (0.32–3.39)	29.01 (8.8–95.62)
	Dysphagia	10017947	1063	6.39 (6.01–6.79)	6.34 (5.97–6.74)	4686.607	2.64 (2.54–2.72)	6.23 (5.86–6.62)
	Constipation	10017947	1295	3.19 (3.02–3.37)	3.17 (3–3.34)	1906.342	1.65 (1.57–1.73)	3.14 (2.98–3.32)
	Faeces hard	10017947	28	3.83 (2.64–5.57)	3.83 (2.64–5.57)	57.89216	1.92 (1.25–2.33)	3.8 (2.62–5.51)
	Abdominal discomfort	10017947	751	2.18 (2.03–2.34)	2.17 (2.02–2.33)	472.027	1.11 (1–1.22)	2.16 (2.01–2.32)

Note: SOC:system organ class, PTs:preferred terms.

3.3. Age subgroup analysis

We performed subgroup analyses according to age for the neurological, gastrointestinal, and psychiatric categories of interest. The results showed that among all adverse reactions with statistical differences (P < 0.05), restless legs syndrome occurred more frequently in patients aged ≤65 years than in those aged >65 years. However, ageusia, dementia, amnesia, balance disorder, dizziness, confusing state, eating disorder, and dysphagia rarely occurred (Table 3).

Table 3. Comparison of signal strength at SOC and PT levels for different age groups (≤65 vs >65).

SOC Name	PTs	a	b	c	d	statistical methods	Statistics	P
Nervous system disorders	Restless legs syndrome	27	10636	75	64856	Chi-Square	12.889	0.000
	Hypogeusia	1	10662	15	64916	Chi-Square Continuity Correction	0.296	0.587
	Spinal cord compression	7	10656	20	64911	Chi-Square Continuity Correction	2.215	0.137
	Ageusia	3	10660	114	64817	Chi-Square	12.883	0.000
	Dysgeusia	34	10629	280	64651	Chi-Square	2.796	0.095
	Normal pressure hydrocephalus	0	10663	2	64929	Fisher’s precision probability test	0.000	1.000
	Hypersomnia	8	10655	123	64808	Chi-Square	6.930	0.008
	Dementia	1	10662	91	64840	Chi-Square	12.885	0.000
	Amnesia	41	10622	213	64718	Chi-Square	0.872	0.350
	Balance disorder	22	10641	269	64662	Chi-Square	10.330	0.001
	Dizziness	145	10518	1252	63679	Chi-Square	16.311	0.000
	Seizure like phenomena	3	10660	7	64924	Chi-Square Continuity Correction	0.980	0.322
Psychiatric disorders	Laziness	1	10662	8	64923	Chi-Square Continuity Correction	0.000	1.000
	Initial insomnia	6	10657	26	64905	Chi-Square Continuity Correction	0.251	0.616
	Confusional state	44	10619	404	64527	Chi-Square	6.827	0.009
	Eating disorder	3	10660	65	64866	Chi-Square	5.279	0.022
Gastrointestinal disorders	Malignant dysphagia	0	10663	2	64929	Fisher’s precision probability test	0.000	1.000
	Dysphagia	35	10628	507	64424	Chi-Square	26.355	0.000
	Constipation	99	10564	712	64219	Chi-Square	2.439	0.118
	Faeces hard	1	10662	13	64918	Chi-Square Continuity Correction	0.133	0.715
	Abdominal discomfort	70	10593	358	64573	Chi-Square	1.798	0.180

Note: SOC:system organ class, PTs:preferred terms, a:Number of people aged ≤ 65 with target adverse reactions, b:The number of people ≤65 years old who do not have target adverse reactions. c:Number of people aged > 65 with target adverse reactions, d:The number of people >65 years old who do not have target adverse reactions.

4. Discussion

Compared with first-generation AR antagonists, enzalutamide exhibits a higher affinity for AR and has a greater propensity for binding. Additionally, enzalutamide can inhibit intramolecular or intermolecular N-terminal transactivation domain-C-terminal ligand-binding domain interactions, thereby impeding receptor translocation to the nucleus and subsequently blocking signal activation [10]. In 2012, the US FDA approved enzalutamide as a therapeutic agent for the treatment of mCRPC after docetaxel chemotherapy, which was subsequently approved as a first-line treatment for patients with mCRPC in 2014 [11]. Upon the initiation of enzalutamide therapy, patients may experience various adverse reactions. tour study identified and analyzed these adverse events using the FAERS database. Our investigation uncovered adverse reactions that were not explicitly indicated in the enzalutamide labeling, namely hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorder, seizure-like phenomena, confusion, eating disorders, and dysphagia.

Moreover, a previous case report documented taste alterations in a patient with prostate cancer after 6 weeks of enzalutamide treatment, which dysgeusia improved when drug administration was shifted from morning to evening [12]. A study published in The New England Journal of Medicine reported instances of seizures following enzalutamide use in patients with castration-resistant prostate cancer [13]. In addition, another study observed that seizures occurred after enzalutamide treatment [7]. Furthermore, a phase IV clinical trial documented the occurrence of amnesia, cognitive disorders, memory impairment, and confusion following enzalutamide administration [14]. Although these studies partially support our findings, to the best of our knowledge, our research was the first to determine the novel associations with normal-pressure hydrocephalus, dementia, balance disorders, eating disorders, and dysphagia. These findings warrant further investigation.

Furthermore, our analysis revealed several adverse reactions that are indeed mentioned in the enzalutamide drug instructions, including fatigue (n = 7186), back pain (n = 1609), constipation (n = 1295), muscular weakness (n = 656), spinal cord compression (n = 38), hematuria (n = 164), and dizziness (n = 2220) [15,16]. These findings highlight the significance of our study.

This study had limitations. First, the FAERS database does not establish a definitive causal relationship between adverse events and drugs without comprehensive data on drug-related adverse events. Consequently, our ability to conduct a thorough analysis and calculate the incidence of adverse reactions accurately was limited. Second, our data mining efforts relied solely on the FAERS database and did not incorporate other data sources, thereby imposing limitations on the scope of our analysis.

Nevertheless, our study can be used as a reference for future research in determining adverse drug reactions. However, determining adverse reactions for each drug in the real world is a complex and ongoing process that requires continuous research and exploration by investigators.

5. Conclusion

This study observed several adverse reactions in the patient’s nervous system after enzalutamide administration, including hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorders, and seizure-like phenomena. Additionally, mental symptoms, such as laziness, confusion, and eating disorders have been reported. Gastrointestinal manifestations, such as dysphagia, constipation, hard feces, and abdominal discomfort, were also observed. These findings, spanning the nervous system, mental, and gastrointestinal aspects, underscore the importance of vigilant monitoring and tailored patient care. Integrating these insights into clinical practice could contribute to informed decision-making; however, further research is imperative to validate and establish the broader relevance of our findings.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contributions

Study concept and design: X Wang, W Zhang, and L Chang. Acquisition of the data: L Chang, Z Ma, Y Jiang and Z Li. Analysis and interpretation of the data: Z Li, L Chang, Y Chen and Z Ma. Drafting of the manuscript: W Zhang and X Wang. Statistical analysis: L Chang, X Ren, X Jia and Z Ma. Technical support: X Ren, Z Li, Q Wang and X Wang. All the authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Acknowledgments

We would like to thank the Food and Drug Administration Adverse Event Reporting System.

Data availability statement

The data that support the findings of this study are available in FAERS at: https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysis

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2255524

Additional information

Funding

This work was supported by Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province under Grant [20210005]; Applied Basic Research Project of Shanxi Province under Grant [20210302124611]; and Shanxi Scholarship Council under Grant [2021-164].