Does the initial dose of enzalutamide affect the incidence of adverse events in CRPC patients?

Editor's comment: Prostate cancer is currently the second most common male malignant tumor in the world.
Studies have shown that after a median of 12 months of endocrine therapy in patients with advanced prostate cancer, almost all patients will progress to castration-resistant prostate cancer (CRPC) [ 1]
.

In recent years, with continuous breakthroughs and progress in clinical research, surgical treatment, endocrine therapy and immunotherapy can all be used as clinical treatments for CRPC, but new endocrine therapy is still one of the most common clinical treatments for CRPC
.

Enzalutamide is one of the new endocrine drugs, and its original drug has been approved by the National Medical Products Administration (NMPA) in China for use in non-metastatic castration-resistant prostate cancer (NM-CRPC) adult patients and males with a high risk of metastasis.
Treatment of adult patients with metastatic castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic and have not received chemotherapy after the failure of hormone deprivation therapy (ADT)
.

In order to reduce the incidence of adverse events (AEs) of enzalutamide, researchers conducted a series of discussions
.

So, can reducing the initial dose of enzalutamide reduce the incidence of AEs? Recently, a study published in the journal PLOS ONE discussed the relationship between the initial dose of enzalutamide and the incidence of AEs [2]
.

01 Research Introduction The trial is a retrospective analysis that collected 233 cases of CRPC treated with enzalutamide in the Affiliated Hospital of the Tokyo Jiekai Medical University and the Affiliated Hospital of the University of Ryukyus School of Medicine between June 2014 and December 2018.
Patient's clinical data
.

After 1:3 propensity score matching (PSM), 124 patients were randomly divided into a reduced-dose group and a standard-dose group, and compared the prostate-specific antigen (PSA) of patients under different initial doses of enzalutamide.
Change and incidence of AEs
.

Among them, 190 (81.
6%), 25 (10.
7%), 15 (6.
4%) and 3 (1.
3%) patients received 160, 120, 80 and 40 mg of enzalutamide, respectively
.

After 1:3 PSM, there were 31 and 93 patients in the reduced-dose group and the standard-dose group, respectively
.

02 The results of the study showed a median follow-up of 17 months.
After enzalutamide treatment, the average reduction of PSA in the standard-dose group was significantly higher than that in the reduced-dose group, which were -87.
4% and -66.
3%, respectively (p=0.
02)
.

The proportion of patients with a PSA drop of >90% in the standard dose group was significantly higher than that in the reduced dose group, which were 46.
2% and 25.
8% (p=0.
03)
.

Overall, a total of 84 patients (67.
7%) experienced PSA progression, and 24 patients (19.
4%) experienced death from any cause
.

At the same time, the median time to PSA progression in the standard-dose group was longer than that in the reduced-dose group, and the difference was not statistically significant (8 months and 6 months, respectively, p=0.
10, Figure 1 and Figure 2)
.

Figure 1 The therapeutic effect of different initial doses of enzalutamide Figure 2 PSA changes In the overall cohort, the incidence of any grade of AEs and grades 3-5 AEs were 30.
2% and 8.
9%, respectively.
The most common AEs were fatigue and appetite Decrease (Figure 3)
.

At the same time, the researchers found that there was no significant difference in the incidence of any grade AEs and grade 3-5 AEs between the standard dose group and the reduced dose group (34.
4% and 22.
6%, 9.
7% and 6.
5%, p=0.
24 and 0.
61, respectively)
.

Figure 3 AEs reported in the standard dose group and the reduced dose group According to the above test results, reducing the initial dose of enzalutamide does not significantly reduce the incidence of AEs, and the PSA remission rate is lower than that in the standard dose group
.

Summary In the previous dose escalation studies (30~360mg/day), the dose dependence of enzalutamide was observed
.

The results showed that patients who took 60 mg of enzalutamide a day had a >50% decrease in PSA than those who took a higher dose (>150 mg) a day
.

At the same time, the study observed the dose-dependence of enzalutamide on the incidence of AEs.
Patients who took 150mg of enzalutamide daily did not stop treatment due to AEs
.

Therefore, based on this study [3], the standard dose of enzalutamide is set at 160 mg per day
.

However, in real-life treatment, patients may request to reduce the initial dose of enzalutamide because of concerns about AEs
.

Through this study, we found that the incidence of AEs of enzalutamide has nothing to do with dose
.

At the same time, if the patient continues to take less than the standard dose of enzalutamide, the remission of PSA is not optimistic, that is, reducing the initial dose of enzalutamide will not reduce the incidence of AEs, but will also affect enzalutamide.
The curative effect
.

Therefore, in clinical practice, standard-dose enzalutamide treatment is still recommended for CRPC patients
.

References: [1] Gao Xu, Sun Yinghao.
Progress in the treatment of non-metastatic castration-resistant prostate cancer[J].
Chinese Journal of Urology,2019,40(11):868-872.
[2] Tsuzuki S, Nakanishi S, Tamaki M, et al.
Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer.
PLoS One.
2021 Oct 1;16(10):e0258160.
[3] Scher HI, Beer TM , Higano CS, et al.
Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium.
Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.
Lancet.
2010 Apr 24;375(9724):1437 -46.