Efficacy and safety of abiraterone and enzalutamide
Efficacy and safety of abiraterone and enzalutamide for castration-resistant prostate cancer: A systematic review and meta-analysis of randomized controlled trials
Xiaonan Zheng, MD, Xiaohui Zhao, MD, Hang Xu, MD, Xin Han, MD, He Xu, MD, Xin Dong, MD, Ruilin Peng, MD, Lu Yang, MD, Qiang Wei, MD, Jianzhong Ai, PhD
Previous evidence directly evaluating the efficacy and safety of abiraterone and enzalutamide treatment for castration-resistant prostate cancer (CRPC) is limited. We aim to include more randomized controlled trials (RCTs) to comprehensively assess the efficacy and safety of abiraterone and enzalutamide treatment.
PubMed, Embase, and ClinicalTrial.gov were systematically searched. Pooled hazard ratios (HRs) were calculated using Stata 12.0 software. The comparison of the prostate-specific antigen (PSA) response rate and adverse events (AEs) between the treatment and control groups were performed using RevMan 5.3 software.
Eight eligible RCTs with 6,490 patients were selected. Pooled HRs were 0.72 for overall survival, 0.45 for radiographic progression-free survival (rPFS), and 0.36 for PSA PFS. abiraterone and enzalutamide could significantly increase the PSA response rate OR = 8.67, 95%CI 4.42–17.04) and any AE occurrence (OR = 1.98, 95%CI 1.46–2.68). The treatment group had more occurrence of fatigue (OR = 1.34, 95%CI 1.20–1.49), back pain (OR = 1.15, 95%CI 1.01–1.15), hot flush (OR = 1.76, 95%CI 1.50–2.06), diarrhea (OR=1.22, 95%CI 1.07–2.40) and arthralgia (OR = 1.34, 95%CI 1.16–1.54). Particularly, AEs of special interest including any grade hypertension (OR = 2.06, 95%CI 1.71–2.47), hypokalemia (OR = 1.80, 95%CI 1.42–2.30) and fluid retention or edema (OR = 1.38, 95%CI 1.17–1.63) also occurred less in the control group. Moreover, a higher incidence of high-grade hypertension (OR = 2.60, 95%CI 1.79–3.79) and extremity pain (OR = 4.46, 95%CI 2.81–7.07) was observed in the treatment group.
The survival benefits of abiraterone and enzalutamide for CRPC were evident and promising, while the risk of AE occurrence was also acceptably higher in the treatment group than in the placebo group.
Prostate cancer is one of the most common cancers in men worldwide.[1,2] Regardless of the indolent course of many tumors and excellent prognosis of localized prostate cancer, advanced prostate cancer is fatal. Androgen deprivation therapy is the standard treatment for advanced prostate cancer. Most patients initially respond to castration, but the disease will eventually progress; a tumor escape mechanism is believed to be employed by castration-resistant prostate cancer (CRPC) to overcome androgen deprivation therapy and cause subsequent mortality.
Abiraterone and enzalutamide are two new androgen receptor (AR) inhibitors for the treatment of CRPC. As a selective inhibitor of androgen biosynthesis, abiraterone acetate can irreversibly and potently block CYP17, a crucial enzyme in testosterone and estrogen synthesis, resulting in virtually undetectable serum and intratumoral androgens,[6,7] while enzalutamide can reduce the efficiency of its nuclear translocation and impair both DNA binding to androgen response elements and recruitment of coactivators.[7,8] With different mechanisms, both AR inhibitors are new options in CRPC treatment. The COU-AA-301, COU-AA-302,[10,11] AFFIRM, and PREVAIL trials have promoted the use of abiraterone and enzalutamide, and several subsequent trials also evaluated their efficacy. However, few meta-analyses have included all related randomized clinical trials (RCTs) and directly pooled the hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) of these two agents. Additionally, although some previous studies have attempted to investigate the efficacy and safety of abiraterone and enzalutamide, pooled evidence was limited, and their analyses were either indirect or subjected to bias caused by non-RCTs.[14–17] Moreover, the comparison of the occurrence of high-grade adverse events (AEs) (grade ≥ 3) between the AR inhibitor and control groups has been insufficient.
In this meta-analysis, we aim to confirm the efficacy and safety of AR axis-signaling targeting agents by directly calculating the pooled HRs of OS and PFS and pooled odds ratio (OR) of prostate-specific antigen (PSA) response rate in the abiraterone and enzalutamide treatment group compared with those in the control group. Meanwhile, the occurrence of AEs (overall and high-grade) was compared between the AR inhibitor and control groups. Furthermore, a subgroup analysis was conducted to compare abiraterone and enzalutamide treatments.
2. Patients and methods
2.1 Search strategy and inclusion criteria
This systematic review and meta-analysis was conducted according to the PRISMA guidelines. Two investigators independently searched PubMed, Embase, and ClinicalTrials.gov for phase 2 and 3 RCTs published until August 1, 2018. The search strategy included the following terms: “castration-resistant prostate cancer,” “CRPC,” “androgen receptor,” “CYP17A1,” “cytochrome P450 17A1,” “abiraterone,” “enzalutamide,” “efficacy,” “survival,” “safety,” and “adverse.” References cited by the finally selected articles were also reviewed.
RCTs assessing the efficacy and safety of AR inhibitors, CYP17A1 inhibitor in patients with CRPC, and providing data on HRs with 95% confidence intervals (95% CIs) were potentially eligible. The detailed inclusion criteria were as follows:
2) evaluation of abiraterone and/or enzalutamide efficacy against a control;
3) use of abiraterone or enzalutamide in the experimental group rather than in the control group;
4) report of efficacy indicators, including OS and/or PFS, or AEs;
5) available HR and 95% CI on efficacy; and
6) publication in the English language.
We excluded articles
that were non-RCTs and not published in the English language;
that did not either assess the efficacy or report the AEs of abiraterone and enzalutamide;
in which other agents that might deviate the conclusion were used in the experimental group;
in which abiraterone and enzalutamide were used together in the experimental group; and
in which abiraterone and enzalutamide were regarded as the control group. Duplicate articles from the same RCT were screened and excluded.
2.2 Data analysis
Two investigators independently extracted data from the included articles, and all members of our team resolved the discrepancies by consensus. Data include the clinical trial code (National Clinical Trial), study name, study phase, study size, drugs used in the experimental and control groups, median age, percentage of patients with PSA decline ≥ 50%, definition of PFS, and median OS and PFS.
The primary outcome was the efficacy of abiraterone and enzalutamide on the enrolled patients, for which pooled HRs of PFS and OS were calculated using the random-effects model. Moreover, PSA response rate (defined as at least 50% PSA decline from baseline) was compared between the treatment and control groups. A subgroup analysis of PFS according to the type of AR inhibitors was also conducted. Heterogeneity between different AR inhibitors was assessed. Pheterogeneity < .05 was regarded as statistically significant.
The second outcome was the comparison of aggregated AE statistics (any AE, high-grade AE [grade ≥ 3], AE leading to death, AE leading to discontinuation, and any severe AE) and the occurrence of any grade AE, AE of special interest, and high-grade AE (grade ≥ 3) between the treatment and control groups. To maximally eliminate the potential bias caused by various reporting standards of AE occurrence in these selected trials, we extracted data on AEs that occurred in at least 10% of either the treatment or control group. Furthermore, to make our data more statistically powerful and the conclusion more convincing, AEs reported in at least 3 trials were included for comparison. In the forest plot for comparison, when the points of the diamond did not overlap the vertical line, a significant difference between the treatment and control groups was indicated.
Q test and I2 were employed to evaluate the heterogeneity between studies. When a high heterogeneity (I2 > 50%) was noted between studies, a sensitivity analysis was conducted to determine the source of heterogeneity using the following steps: remove each trial in the analysis and recalculate the heterogeneity. When the heterogeneity remained high after trials were individually removed, we analyzed the trials themselves and determined the reasonable sources of high heterogeneity.
All mentioned analyses were conducted using Stata software (version 12.0), and images were processed with Photoshop (version CS6).
2.3 Quality assessment
The methodological quality of the included trials was assessed using the Jadad ranking system. An RCT could be given a Jadad score of between 0 (poor) and 5 (optimal) according to the quality of randomization, double-blinding, and follow-up.
3.1 Study characteristics
From 963 retrieved publications, we selected 84 potentially eligible articles for abstract and full article review. Eventually, 8 RCTs with 10 articles, which were published from 2012 to 2017, met the inclusion criteria[9–13,20–24] (Fig. 1 and Table 1). Two trials were phase 2 while 6 trials were phase 3. Five were first-line trials, and three were second-line trials (Table 1). For each trial, the number of patients with CRPC ranged from 214 to 1199, and a total of 6490 patients were included. A total of 1639 patients (25.3%) were enrolled in the abiraterone plus prednisone group and 2053 (31.6%) in the enzalutamide group, while 1165 patients (17.9%) were enrolled in the prednisone plus placebo group, 398 patients (6.1%) were enrolled in the bicalutamide group, and 1244 patients (19.1%) were administered only the placebo. The median age of the enrolled patients varied from 68 to 74 years, with two trials reporting mean ages.