Abstract
Background/Aim: It has been reported that some adverse events (AEs) of enzalutamide (ENZ) occur more frequently in Japanese patients with castration-resistant prostate cancer (CRPC) due to higher steady-state trough plasma concentrations of ENZ (CSS, ENZ) and its active metabolite (NDE), (CSS, NDE). Thus, we investigated the efficacy, safety, and pharmacokinetics of ENZ in Japanese patients with CRPC. Patients and Methods: Fourteen patients were administered ENZ at a standard dose (160 mg/day) or reduced doses (80 or 120 mg/day). Prostate-specific antigen (PSA), AEs, CSS, ENZ, and CSS, NDE were examined. Results: A maximum PSA decrement of ≥50% from baseline was achieved in 92% of patients. AEs were few (>20%) and mild. No differences in CSS, ENZ and CSS, NDE between other ethnic groups in previous literature and our subjects was observed. Conclusion: ENZ shows adequate efficacy and safety in Japanese patients with CRPC, even if administered at reduced doses in real-world conditions.
- Enzalutamide
- N-desmethyl enzalutamide
- castration-resistant prostate cancer
- pharmacokinetics
- reduced dose
Enzalutamide (ENZ) is an oral antiandrogen approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), which acts by competitively inhibiting the androgen receptor (AR) signaling pathway at multiple steps, including androgen binding to the cytoplasmic AR, nuclear translocation of the AR, nuclear AR binding to DNA, and AR binding to its coactivator (1).
The clinical efficacy and safety of ENZ at the recommended standard dose of 160 mg/day were established in both chemotherapy-naive and post-chemotherapy patients with metastatic CRPC by two randomized, placebo-controlled, multicenter, phase III clinical trials (i.e., AFFIRM and PREVAIL trials) (2, 3). However, adverse events (AEs) such as fatigue, constipation, and decreased appetite have been reported in most patients on a maintenance dose of 160 mg/day (2-11). Hence, physicians tend to select reduced doses of ENZ (e.g., 80 or 120 mg/day) in clinical practice (11-17).
In a previous study, 16β-18F-5α-dihydrotestosterone positron emission tomography imaging showed a high affinity of ENZ for the AR at 60-360 mg/day (18). Furthermore, ENZ doses higher than 150 mg/day were found to have no additional effect on the magnitude of prostate-specific antigen (PSA) decline, despite resulting in higher steady-state trough plasma concentrations of ENZ (CSS, ENZ) (18). These results suggest that reduced doses of ENZ, too, might prove clinically efficient.
ENZ is metabolized predominantly by cytochrome P450 (CYP) 2C8 and partially by CYP3A4/5 to N-desmethyl ENZ (NDE) and ENZ carboxylic acid (19, 20). NDE is assumed to contribute to the clinical effects of ENZ because it displays almost the same affinity for the AR as does ENZ in in vitro assays, whereas ENZ carboxylic acid possesses relatively little pharmacological activity (20, 21).
A subanalysis of the PREVAIL trial in Japanese patients found AEs including decreased appetite, weight loss, and back and cancer pain to be more common in Japanese than in non-Japanese patients, which was attributed to slightly higher CSS, ENZ and CSS, ENZ + steady-state trough plasma concentrations of NDE (CSS, NDE) in Japanese patients compared to non-Japanese ones, due to their lower body weights (22).
However, no real-world cohort study has been performed so far to carefully explore the effects of ENZ on Japanese patients. Hence, the present study was designed to scrutinize the efficacy, safety, and pharmacokinetics of ENZ in Japanese CRPC patients.
Patients and Methods
Patients and study design. Ethical approval for this study was obtained from the ethics committees of Gifu Pharmaceutical University (No. 30-43) and Gifu Municipal Hospital (No. 482).
CRPC patients aged 50 years or over for whom ENZ therapy was initiated at the Gifu Municipal Hospital (Gifu, Japan) between October 2018 and February 2020 were eligible for study inclusion. Patients already on ENZ therapy, those with symptoms similar to the AEs caused by ENZ (including fatigue, nausea, or seizure) within 2 weeks before ENZ initiation, and those considered ineligible by their physician were excluded from the study.
The eligible patients received 80, 120, or 160 mg of oral ENZ once daily. Blood samples were collected at 2 and 4 weeks after treatment initiation, followed by regular monthly visits thereafter. The samples were centrifuged, and plasma was separated and stored at –80°C until further analysis. CSS, ENZ and CSS, NDE were measured using a validated high-performance liquid chromatography method established in our laboratory (23). As suggested by previous reports, CSS, ENZ and CSS, NDE were evaluated 3 months after ENZ treatment (19, 21). In cases with altered dosing regimens, CSS, ENZ and CSS, NDE were evaluated 3 months after dose alterations.
Data on patients’ demographics, ENZ dose regimens, prior treatment, concomitant drugs, laboratory data, PSA levels, and AEs were collected from electronic medical records, treatment diaries, and diagnostic interviews. Informed consent was obtained from all individual participants included in the study.
Evaluations. The efficacy of ENZ was evaluated by the PSA response rate (i.e., a decline of ≥50% from baseline, 3 months after treatment initiation). According to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (24), PSA progression was defined as an increase in PSA ≥25% (2 ng/ml) above the nadir, which was confirmed by a second reading at least 3 weeks later. All AEs were classified based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. The incidence of AEs was designated by grades increasing from baseline.
Results
Patient characteristics. As shown in Figure 1, a total of 18 patients were enrolled in the present study. Baseline demographics and characteristics are summarized in Table I. The median age, body weight, baseline PSA, and treatment duration were 79 years, 64.4 kg, 10.1 ng/ml, and 8.3 months, respectively. Although the majority of cases continued treatment with ENZ, five patients were discontinued from treatment due to rash (n=1), fatigue (n=1), PSA progression (n=2), and progressive disease (n=1). Notably, before treatment initiation, 11 patients were diagnosed with hypertension (all grades, 79.0%; Grade ≥3, 14.3%), and seven patients took antihypertensive drug(s).
CONSORT diagram.
Patient characteristics.
Regarding concomitant drug(s), one patient received clopidogrel – a CYP2C8 inhibitor – whereas no other patients received concomitant drugs inducing or inhibiting ENZ metabolism.
Effect of ENZ on PSA levels. After 3 months of ENZ treatment, 12 patients (92.3%) exhibited a maximum PSA decrease of ≥50% from baseline, nine of whom (69.2%) experienced a maximum PSA decline of ≥90% (Table II). There was no clear relationship between ENZ doses and PSA response rates (Figure 2). Furthermore, two patients showed PSA progression, one within 3 months of treatment with ENZ (80 mg/day) and the other 7.2 months after treatment initiation, although a good PSA response was observed in the latter (Figure 2; patient No. 9). PSA flare was observed in two patients (Figure 2; patients No. 3 and 4). The median time to progression-free survival could not be calculated (Figure 2; the Kaplan–Meier curve).
Waterfall plot of maximum percent change from baseline of prostate-specific antigen and the Kaplan–Meier estimates of the time to PSA progression and/or radiographic progression-free survival. The dotted lines show the defined degree of decline.
PSA response at 3 months.
Steady-state trough concentrations of ENZ and NDE in plasma. CSS, ENZ and CSS, NDE at 3 months after treatment initiation are shown in Figure 3 and summarized in Table III. The mean CSS, ENZ and CSS, NDE were dose-dependently increased up to 13.0 and 13.1 μg/ml, respectively, at 160 mg/day.
Plasma concentrations of enzalutamide (ENZ) and the sum of the two (ENZ plus N-desmethyl enzalutamide; NDE) are presented in patients with CRPC 3 months after starting ENZ. The dotted lines show mean concentrations in plasma. One patient was excluded since the duration of treatment was >3 months.
Steady-state trough concentration of enzalutamide and N-desmethyl enzalutamide in plasma.
CSS, ENZ and CSS, NDE in two patients, one using clopidogrel (a CYP2C8 inhibitor) and the other suffering from renal failure (baseline estimated glomerular filtration rate, 26.2) did not appear to be different from those in other patients.
AEs caused by ENZ. Some AEs were observed in all patients, with the most frequent ones (incidence ≥20%) being constipation (36%), weight loss (21%), hypertension (50%), and thrombopenia (29%) (Table IV). However, many of these AEs were mild (below Grade 3). Although four patients showed serious hypertension (Grade 3), their ENZ treatment was continued beyond 3 months with the help of appropriate antihypertensive medications. Fatigue, one of the major AEs caused by ENZ (2-4, 6, 8, 25, 26), occurred in two patients within less than 1 month after treatment initiation with 160 mg/kg of ENZ.
Adverse events.
Discussion
This study aimed to investigate the efficacy and safety of ENZ in a real-world cohort of Japanese patients with CRPC. ENZ showed high PSA response rates, which were indicative of better efficacy. Our results suggest that ENZ is a well-tolerated treatment option for CRPC in Japanese patients although physicians select its reduced doses.
Although 71.4% of the patients in this study were administered reduced doses of ENZ due to their age and past medical history (e.g., cerebral infarction and polypharmacy), the efficacy of ENZ as represented by PSA response rates was found to be better than that reported in previous studies, where the standard dose of ENZ (i.e., 160 mg/day) was commonly used (2, 3, 6, 7, 10, 11, 16, 25, 27-32). One possible reason for the efficacy of reduced ENZ doses is that CSS, ENZ might suffice to treat CRPC. As mentioned above, a minimum CSS, ENZ of 5.0 μg/ml could be considered as a target for exposure to ENZ (33), because AR binding with CSS, ENZ of 11.4 μg/ml was higher than that with 5.0 μg/ml (18). Indeed, CSS, ENZ in all our patients treated with ENZ turned out to exceed 5.0 μg/ml. Another possible reason for the efficacy of reduced ENZ doses is the low level of baseline PSA in our cohort. A previous study reported the baseline PSA level as one of the crucial factors in determining the effects of ENZ therapy on Japanese patients (11). That is, the median baseline PSA level in CRPC patients with a PSA decline of >50% was 23.4 ng/ml, which was relatively lower than that in cases with a PSA decrease of <50% (median, 41.5 ng/ml) (11). Instead, the median baseline PSA level in the present study was 10.1 ng/ml. Taken together, our results indicate that ENZ would prove effective in treating CPRC even if its dose is reduced. In order to understand the underlying mechanisms further, it would be needed to investigate other factors to affect PSA response such as serum γ-glutamyl transferase (34).
Regarding AEs, serious hypertension (Grade ≥3) was observed here, which is consistent with several past studies, where ENZ was shown to worsen hypertension (3, 6, 8, 9). Furthermore, Grade 3 hypertension was properly controlled with antihypertensive medications and therefore, did not lead to discontinuation of ENZ therapy. Therefore, AEs caused by ENZ therapy would be mild and tolerable in a real-world cohort of Japanese CRPC patients, although appropriate care should be delivered to those diagnosed with hypertension.
Fatigue has been reported as the most frequent AE in patients on ENZ (2-9). Indeed, Grade 1 or 2 fatigue was observed in ≥30% of patients treated with ENZ (160 mg/day) in previous studies (2-4, 6, 8, 25, 26). In the present study, only 14% of the patients (n=2) experienced fatigue, both of whom had been administered ENZ at an initial dose of 160 mg/day. Conversely, none of the patients treated with 80 and 120 mg/day of ENZ suffered fatigue. This is partially in agreement with previous studies showing the relationship between fatigue and ENZ doses (16, 18, 19). Furthermore, although weight loss (overall, 25%; Grade ≥3, 3.6%) and decreased appetite (overall, 25%; Grade ≥3, 0%) are reportedly more frequent in Japanese patients than in those of other races (22), they both appeared to be milder with lower frequencies in the present study. Hence, ENZ dose reduction might diminish the severity and occurrence of AEs. Nevertheless, the fact that AEs were also observed in patients treated with 80 or 120 mg/day of ENZ underscores the necessity of considering AEs even when reduced doses of ENZ are administered.
A previous study found slightly higher CSS, ENZ and CSS, ENZ + CSS, NDE in Japanese than in non-Japanese patients, which were assumed to have subsequently caused higher incidences of AEs in Japanese patients (22). By contrast, CSS, ENZ and CSS, ENZ + CSS, NDE for our patients who received 160 mg/day of ENZ were lower than those for the Japanese patients in the PREVAIL trial and similar to those for non-Japanese patients (22). However, the adjusted CSS, ENZ and CSS, ENZ + CSS, NDE at 160 mg/day of all patients in the present study were almost similar to CSS, ENZ and CSS, ENZ + CSS, NDE in Japanese patients in the PREVAIL trial (22). Indeed, the decreased clearance of ENZ was observed in patients treated with 80 or 120 mg/day of ENZ as expressed by the increased ratio of CSS, ENZ and CSS, ENZ + CSS, NDE to the dose of ENZ. These results suggest that the dose reduction by physicians in the present study successfully controlled the levels of CSS, ENZ and CSS, NDE.
No apparent drug–drug interaction of ENZ with concomitant drugs was observed. That is, although ENZ is mainly metabolized by CYP2C8 and CYP3A4/5 (19, 20), clopidogrel, whose glucuronate conjugate acts as a CYP2C8 inhibitor (35-37), did not affect CSS, ENZ and CSS, NDE. Furthermore, no alteration in CSS, ENZ and CSS, NDE in one patient with renal impairment was observed. These results suggest that the ENZ might be easily applicable to elderly patients with CRPC receiving other drugs and/or with renal impairment.
Notably, our study has some limitations. The small number of enrolled patients represents a crucial limitation. Furthermore, the duration of ENZ treatment was still shorter (8.3 months) than that in previous reports (6, 8, 9, 16, 25). For example, as reported in the PREVAIL trial for metastatic CRPC (3) and the PROSPER trial for non-metastatic CRPC (8), the 50% decline in PSA progression-free survival was 11.2 and 37.2 months, respectively. Thus, a further observation period would be required to evaluate the efficacy of ENZ thoroughly in Japanese patients with CRPC.
Conclusion
In conclusion, CSS, ENZ and CSS, NDE were within the expected range. Additionally, ENZ was shown to have adequate efficacy and safety in CRPC patients, even if administered at reduced doses. The present study is still ongoing, and therefore, the relationship of CSS, ENZ and CSS, NDE with ENZ effectiveness and safety should be further investigated.
Footnotes
↵* These Authors contributed equally to this study.
Authors’ Contributions
AH and HS equally contributed as first authors. AH, TM, CG, and KK designed the study. AH collected the clinical data. HK were contributed to clinical analysis, and HS, SS, EM, MA, AA and MS measured plasma concentrations of ENZ. AH, HS, MS, and KK drafted the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received October 9, 2020.
- Revision received October 19, 2020.
- Accepted October 20, 2020.
- Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
