Additionally, we also conducted a subgroup analysis according to the different types of AR inhibitors (Supplementary Figures S1, S2, and S3, http://links.lww.com/MD/D328). It seemed that enzalutamide had greater efficacy than abiraterone in either rPFS (HR, 0.36 vs 0.60; Pheterogeneity < .05), PSA PFS (HR, 0.24 vs 0.57; Pheterogeneity < .05), or PSA response rate (OR, 21.88 vs 4.69; Pheterogeneity < .05), but not in OS (HR, 0.71 vs 0.78; Pheterogeneity = .319).
3.3 Aggregated AE statistics
As shown Figure 4, the AR inhibitor group had a higher risk of occurrence of overall AE (OR = 1.98; 95% CI, 1.46–2.68; P < .001). However, no significant difference was found between the treatment and control groups regarding the occurrence of high-grade AE, AE leading to death, AE leading to discontinuation, and any severe AE, even though the AR inhibitor group had a virtually significantly lower risk of occurrence of high-grade AE (OR = 0.91; 95% CI, 0.82–1.01; P = .08).
Figure 5A presents the overall AEs with significant difference between the AR inhibitor and control groups. As shown in the forest plots, patients in the treatment group had higher rate of fatigue (OR = 1.34; 95% CI, 1.20–1.49; P < .001), back pain (OR = 1.15; 95% CI, 1.01–1.15; P = .03), hot flush (OR = 1.76; 95% CI, 1.50–2.06; P < .001), diarrhea (OR = 1.22; 95% CI, 1.07–2.40; P = .003), and arthralgia (OR = 1.34; 95% CI, 1.16–1.54; P < .001). No significant difference was observed in the frequency of constipation (OR = 1.13; 95% CI, 0.98–1.29; P = .09) bone pain, extremity pain, anemia, tract infection, and nausea (Supplementary Fig. S4, http://links.lww.com/MD/D328).
Outcomes for AEs of special interest (Fig. 5B), including hypertension (OR = 2.06; 95% CI, 1.71–2.47; P < .001), hypokalemia (OR = 1.80; 95% CI, 1.42–2.30; P < .001), and fluid retention or edema (OR = 1.38; 95% CI, 1.17–1.63; P < .001) all significantly favored the control group.
3.5 High-grade AEs
Regarding high-grade AEs, a higher risk of hypertension (OR = 2.60; 95% CI 1.79–3.79; P < .001) and extremity pain (OR = 4.46; 95% CI 2.81–7.07; P < .001) was observed in the AR inhibitor group (Fig. 5C). There were no significant differences in high-grade fatigue, back pain, constipation, diarrhea, hot flush, fluid retention or edema, urinary tract infection, falls, or decreased appetite between the treatment and control groups (Supplementary Fig. S5, http://links.lww.com/MD/D328).
3.6 Quality assessment
All trials employed randomized treatment allocation sequences, and three trials used computer-generated random numbers or a similar fashion. All trials were double blinded. Jadad scores were provided to each trial and listed in Table 2. The mean score was 4.25, and all trials were ranked as high quality.
In this study, the collected data showed that abiraterone and enzalutamide could provide a maximal median OS of 35.3 months, median PFS of 20 months, and PSA response rate of 90.9%. By calculating the pooled HR, we confirmed that patients diagnosed with CRPC had evidently greater survival benefits after AR inhibitor treatment compared with controls (OS, HR = 0.72; rPFS, HR = 0.45; PSA PFS, HR = 0.36). To our knowledge, this is the first meta-analysis that directly calculated the pooled HRs of OS and PFS of AR inhibitors with the original HR data provided in the trials. A previous study by Fang et al also attempted to pool the HR based on median OS and PFS and a method by Cortes. However, as the authors explained, the estimated HR could bring considerable uncertainty and was weakly convincing.
The PSA response rate was another commonly used marker as an efficacy measure for CRPC response, although the clinical significance of the PSA response rate was not completely clear. Smith reported that a higher PSA response rate was associated with longer survival, even though the meta-analysis by Zheng found inconsistent results. Due to insufficient data in our study, we could not evaluate the correlation between PSA response rate and survival. However, given that our study found that the AR inhibitor group had a significantly higher PSA response rate, we concluded that the efficacy of AR inhibitors for CRPC is quite promising.
Factors associated with response therapy were previously investigated. One of the reported predictive factors of AR inhibitor therapy for CRPC was HSD3B1 gene, the variant type of which was claimed by Shiota to be correlated with lower progression risk and lower all-cause mortality in patients with CRPC receiving abiraterone treatment. Ryan and Penson reported that a higher Gleason score (GS) at initial diagnosis and baseline serum PSA level could also indicate higher risk of disease progression after therapy. Other serum parameters, including lactate dehydrogenase and alkaline phosphatase, were also associated with therapy response, but the outcomes were inconsistent.[9,12,22] Higher scores in scale systems, including Eastern Cooperative Oncology Group (ECOG) performance status and Brief Pain Inventory Short-Form, could also predict higher risk of all-cause mortality. However, it is noted that only the HR for each subgroup with the abovementioned parameters was presented, but the P value was not provided.[9,10,12,22]
The reliability of the efficacy of abiraterone was confirmed by Zhou, and our subgroup outcomes suggested similar conclusions. Moreover, several previous studies had insights into the comparison between abiraterone and enzalutamide. To confirm their conclusions, we also performed a subgroup analysis and evaluated the heterogeneity between abiraterone and enzalutamide. With a limited number of included RCTs, Zhang indirectly compared the OS, PSA PFS, rPFS, and PSA response rate of abiraterone with those of enzalutamide. Consistent to our findings, the study showed that enzalutamide outperformed abiraterone with respect to PSA PFS, rPFS, and PSA response rate. However, there was no significant difference with regard to OS. Similarly, Zheng also found that enzalutamide had greater benefits in PFS but not in OS, although it is an indirect comparison and only two trials were included.
Moreover, we comprehensively explored the safety of abiraterone and enzalutamide by showing that AR inhibitors could lead to higher rates of overall AE occurrence, virtually significantly lower rates of high-grade AE, and similar rates of AE leading to death or discontinuation. Zheng's study also evaluated the safety of abiraterone and enzalutamide, although less AEs occurred. Furthermore, given that only the COU-AA-302 and PREVAIL trials were included in the analysis, the statistical power was relatively low. Our meta-analysis suggested that patients treated with AR inhibitors had a more frequent occurrence of fatigue, back pain, hot flush, diarrhea, arthralgia, hypertension, hypokalemia, fluid retention, or edema. Regarding high-grade AE, hypertension and extremity pain were associated with AR inhibitors. However, the safety of abiraterone and enzalutamide seemed acceptable and controlled, since those AEs could be generally managed by appropriate medical monitoring and our meta-analysis also suggested that they would not lead to more frequent death. Still, those AEs were less fatal compared with AEs caused by cytotoxic therapy. Measures, including a higher dosage of antihypertensive drugs, oral potassium supplementation, and analgesic use, are required to manage these AEs while on AR inhibitor treatment.
Notably, inter-study heterogeneity was generally low, except only in the analyses of PFS, hot flush, hypertension, and hypokalemia, which perhaps could be explained by the different lines of treatment and heterogeneity between abiraterone and enzalutamide.[31,32] Considering that the limitation of our study is relying on published results rather than on the original individual patients’ data, some important baseline characteristics of the patients, that is, age, bone lesion, visceral disease, and ECOG performance status score, along with GS, might also play a crucial role in this substantial heterogeneity. It is likely that other unknown patient characteristics would also cause substantial heterogeneity.
One advantage of this study is the employment of pooled HR to assess the efficacy of AR inhibitors. Compared with the median values of OS and PFS, HR considers both time and cohort size. Furthermore, all data in the analysis were collected from a large population in high quality RCTs. Therefore, our outcomes are more statistically powerful and convincing. Concerning the multiple definitions of PFS, to eliminate the potential bias and make the outcomes more accurate, we categorized PFS into radiographic and PSA-related, which actually had clinical significance. Moreover, as a host of meta-analyses have been conducted to compare abiraterone and enzalutamide, we did not only assess AR inhibitors as a whole but also performed a subgroup analysis to analyze them separately. Moreover, unlike previous meta-analyses, we did not only evaluate the safety of abiraterone and enzalutamide by overall AEs but also focused on high-grade AEs, which is in fact critical and practical since high-grade AEs are more likely to cause mortality, even if we found AR inhibitors to be only associated with more frequent occurrence of high-grade hypertension and extremity pain.
However, limitations of our study also exist. First, the number of included RCTs still seems insufficient, especially in the subgroup analysis comparing abiraterone and enzalutamide, although we have systematically searched available databases and cross-referenced the identified articles. Second, the variations in the included studies, for instance, the baseline PSA level and GS, different inclusion and exclusion criteria, and follow-up therapy, could affect the individual survival outcomes and subsequent pooled outcomes. Third, a substantial heterogeneity was found in some analyses. In our meta-analysis, six trials had first-line setting, and only two had second-line setting. However, Zhang investigated the optimal treatment sequencing using the same second-line setting trials included in our studies, so we did not perform the same analysis. Last, data loss was common when we performed analysis for AE occurrence due to different reporting standards in trials. To minimize the potential bias, we only extracted data strictly meeting our inclusion criteria, causing many AEs to be excluded from the analysis.
Accordingly, in future clinical practice, AR inhibitors should be considered as an efficacious and safe treatment option for patients with CRPC, even though practitioners should pay special attention to the AEs mentioned in our study, particularly high-grade AEs. Moreover, it would be meaningful for investigators conducting the original studies to use a uniformed AE reporting standard for further and deeper data analysis.
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.
Conceptualization: Lu Yang, Qiang Wei, Jianzhong Ai.
Data curation: Xiaonan Zheng, Xiaohui Zhao, Hang Xu, Ruilin Peng.
Formal analysis: Xiaohui Zhao, Hang Xu.
Funding acquisition: Lu Yang, Qiang Wei, Jianzhong Ai.
Investigation: Xin Han, He Xu, Xin Dong.
Methodology: Xiaonan Zheng.
Project administration: Lu Yang, Qiang Wei, Jianzhong Ai.
Resources: Xin Han, He Xu, Xin Dong.
Software: Xiaonan Zheng, Xin Han, He Xu, Xin Dong.
Supervision: Xiaonan Zheng, Xiaohui Zhao, Hang Xu.
Visualization: Xiaonan Zheng.
Writing – original draft: Xiaohui Zhao, Hang Xu.
Writing – review & editing: Xiaohui Zhao, Hang Xu.
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abiraterone (AA); adverse event (AE); enzalutamide (Enza); high-grade adverse event; overall survival (OS); progression-free survival (PFS); prostate-specific antigen (PSA) response
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