Dysgeusia is an adverse effect caused by enzalutamide said to affect 1–5% of patients. The reported management strategies include a temporary drug holiday, the prescription of herbal medicine, and changing the timing of enzalutamide intake from morning to before sleep at night. Case 1: A 72-year-old man developed castration-resistant prostate cancer (CRPC) and was administered enzalutamide. After six weeks of enzalutamide installation, he showed taste alternation, and consequently his dysgeusia increased to grade 2; we therefore changed the medicine intake time from morning to night just before sleep without dose reduction. Four weeks after changing the timing, his dysgeusia had improved. Case 2: A 63-year-old man had developed bone metastatic CRPC, so the combination of Ra-223 and enzalutamide (160 mg/body) was introduced. His serum PSA level had gradually decreased, but dysgeusia appeared, so we changed the timing of enzalutamide intake from morning to night just before sleep without dose reduction. One month after changing the timing, his dysgeusia had improved. We herein report two cases of enzalutamide-induced dysgeusia successfully treated by changing the timing of drug intake from morning intake to just before sleep.

In cancer treatment, many drugs cause dysgeusia as a major adverse effect [1]. Dysgeusia not only necessitates a reduction or stopping cancer treatment but also reduces the nutritional status of cancer patients, harming their poor prognosis. Enzalutamide has been shown to imbue a favorable prognosis in multi-phase CRPC [2-4]. However, some adverse effects, including nausea, fatigue, and dysgeusia, have been reported, as with other CRPC treatment drugs. Efforts to manage the side effects induced by enzalutamide are therefore needed [4, 5]. Dysgeusia affects 1% to 5% of patients receiving enzalutamide.

We herein report two cases of enzalutamide-induced dysgeusia successfully treated by changing the timing of drug intake from the morning to just before sleep.

Case 1

A 72-year-old man was referred to our hospital for his bilateral hydronephrosis. His serum PSA level was 178 ng/mL, and bone scintigraphy showed multiple bone metastases. A prostate needle biopsy revealed a Gleason Score of 4 + 4 = 8. NSE, LDH, and ALP levels were also elevated. In July 2018, combined androgen blockade including leuprorelin and bicalutamide was introduced. Despite some decrease in the PSA level, the PSA nadir was not very low and tended to elevate again, so docetaxel was introduced for six courses. Despite docetaxel treatment, however, the PSA and NSE levels were not markedly decreased, so enzalutamide was introduced. After six weeks of enzalutamide installation, the patient showed Common Terminology Criteria for Adverse Events (CTCAE) grade 1 dysgeusia, which later increased to grade 2, so we changed the medicine intake time from the morning to the night just before sleep without dose reduction. Four weeks after changing the timing, his dysgeusia had improved (Fig. 1).

Fig. 1.

Clinical course of case 1.

Fig. 1.

Clinical course of case 1.

Close modal

Case 2

A 63-year-old man was referred to our hospital for a further examination of his elevated PSA level (919 ng/mL). A prostate needle biopsy revealed a Gleason Score of 5 + 5 = 9. Bone scintigraphy and computed tomography (CT) revealed multiple bone metastases and axillary lymph node metastasis. In November 2017, he started combined androgen blockade including leuproreline acetate and bicalutamide (80 mg/body). His serum PSA level had decreased to 1.16 in March 2018 but gradually increased afterward, so leuprprelin was changed to degarelix, and bicalutamide was stopped. Bone scintigraphy revealed residual bone metastatic lesions, so combination therapy with Ra-223 and enzalutamide (160 mg/body) was introduced. His serum PSA level gradually decreased, but CTCAE grade 2 dysgeusia developed in March 2019. We speculated that the dysgeusia had been induced by enzalutamide. Because his dysgeusia was persistent and enzalutamide showed efficacy in reducing his PSA level, the timing of enzalutamide intake was changed from the morning to the night just before sleep without dose reduction. One month after changing the timing, his dysgeusia had improved (Fig. 2).

Fig. 2.

Clinical course of case 2.

Fig. 2.

Clinical course of case 2.

Close modal

Dysgeusia is a distortion in the sense of taste and is often associated with ageusia, which is a complete lack of taste, and hypogeusia, which is a decrease in taste sensitivity [6]. Dysgeusia can be induced by medication, psychological issues, and a loss of zinc, among other causes. In the present cases, the symptoms appeared between 6 weeks and 7 months after enzalutamide was introduced. On changing the timing of the enzalutamide intake, the symptoms recovered. We therefore speculated that dysgeusia was an enzalutamide-induced adverse event in our cases. A previous study showed that enzalutamide caused dysgeusia in around 1–5% of patients.

The large size of enzalutamide capsules makes oral intake difficult [7]. Furthermore, when enzalutamide capsules are taken, the blood concentration level of enzalutamide is rapidly increased, which might result in decreased appetite and nausea [7]. In June 2018, the form of the drug changed from capsule to tablet in Japan and Germany. We reported that patients who showed a low compliance with enzalutamide due to the difficulty associated with taking large capsules demonstrated an improved compliance and better cancer control when taking the drug in tablet form [7].

With the change of the drug form to a tablet form, the rapid increase in the blood concentration of enzalutamide no longer occurs; however, a considerable number of patients still report nausea and a decreased appetite as adverse events. The management of enzalutamide-induced adverse events is especially important for patients who have obtained good CRPC control. The reported management strategies include a temporary drug holiday, the prescription of herbal medicine, and changing the timing of enzalutamide intake from morning to before sleep at night [8]. Taking the drug before sleep means that the blood concentration is higher when the patient has fallen asleep; thus, the patient does not feel or has a decreased feeling of fatigue and nausea. These methods are also used in the management of patients receiving anti-cholinergic agents for lower urinary tract symptoms [9].

The management of dysgeusia by supplying zinc or further assessment was reported, however, such assessments are useful only for dysgeusia. Changing the timing of intake timing might contribute to other adverse symptoms. We herein report two cases in which enzalutamide-induced dysgeusia was treated by changing the timing of enzalutamide intake from morning to night. Changing the timing of enzalutamide intake might improve dysgeusia induced by enzalutamide.

Due to ethical restrictions, the raw data underlying this paper are available upon request to the corresponding author.

Written informed consent to participate and for publication was obtained from the patient and all methods were followed by the ethical standards of the Declaration of Helsinki.

We declare no conflicts of interest

None.

TK, YM, HU are responsible for the concept and drafted the manuscript.

MY provided the intellectual content and critically reviewed the manuscript.

1.
Mortazavi
H
,
Shafiei
S
,
Sadr
S
,
Safiaghdam
H
.
Drug-related Dysgeusia: A Systematic Review
.
Oral Health Prev Dent
.
2018
;
16
(
6
):
499
507
.
[PubMed]
1602-1622
2.
Beer
TM
,
Armstrong
AJ
,
Rathkopf
D
,
Loriot
Y
,
Sternberg
CN
,
Higano
CS
, et al
Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study
.
Eur Urol
.
2017
Feb
;
71
(
2
):
151
4
.
[PubMed]
0302-2838
3.
Hussain
M
,
Fizazi
K
,
Saad
F
,
Rathenborg
P
,
Shore
N
,
Ferreira
U
, et al
Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer
.
N Engl J Med
.
2018
Jun
;
378
(
26
):
2465
74
.
[PubMed]
0028-4793
4.
Scher
HI
,
Fizazi
K
,
Saad
F
,
Taplin
ME
,
Sternberg
CN
,
Miller
K
, et al;
AFFIRM Investigators
.
Increased survival with enzalutamide in prostate cancer after chemotherapy
.
N Engl J Med
.
2012
Sep
;
367
(
13
):
1187
97
.
[PubMed]
0028-4793
5.
Ryan
CJ
,
Smith
MR
,
de Bono
JS
,
Molina
A
,
Logothetis
CJ
,
de Souza
P
, et al;
COU-AA-302 Investigators
.
Abiraterone in metastatic prostate cancer without previous chemotherapy
.
N Engl J Med
.
2013
Jan
;
368
(
2
):
138
48
.
[PubMed]
0028-4793
6.
Samuel
K
.
Feske MAS, O 114: ffice Practice of Neurology
. 2nd ed.
Philadelphia
:
Elsevier Science
;
2003
. p.
114
.
7.
Takashi Kawahara
SN
.
Yasuhide Miyoshi, Masahiro Yao, Hiroji Uemura: Changing the enzalutamide form from a capsule to a tablet improves the adherence of medicine intake: A case of a significant decrease in the prostate‐specific antigen level and improvement in radiographic findings
.
IJU Case Reports
.
2019
;
2
(
3
):
143
5
.
8.
Tomonori Minagawa
TD
.
Toshiro Suzuki, Manabu Ueno, Takashi Nagai, Teruyuki Ogawa, Hideo Kiyokawa, Osamu Ishizuka: EFFECTIVENESS OF HOCHUEKKITO (JAPANESE HARBAL MEDICINE) FOR GENERAL FATIGUE AFTER INTRODUCTION OF ENZALUTAMIDE IN THREE CASES OF CASTRATION-RESISTANT PROSTATE CANCER
.
Jpn J Urol
.
2019
;
110
(
2
):
5
.
9.
Tsai
KH
,
Hsiao
SM
,
Lin
HH
.
Tolterodine treatment of women with overactive bladder syndrome: comparison of night-time and daytime dosing for nocturia
.
J Obstet Gynaecol Res
.
2017
Nov
;
43
(
11
):
1719
25
.
[PubMed]
1341-8076
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.