Methods A comprehensive literature search was performed using a combination of keywords related to “abiraterone,” “enzalutamide,” “prostate cancer,” and “adverse events.” Phase II–IV randomized controlled trials (RCTs) on abiraterone or enzalutamide for patients with nonmetastatic or metastatic CRPC were included. Outcome measures included (1) any grade cardiac disorder, (2) severe grade cardiac disorder, (3) any grade hypertension, and (4) severe grade hypertension, as defined by the Common Terminology Criteria for Adverse Events. Pairwise meta-analysis and Bayesian network meta-analyses were performed to investigate the risk ratios (RRs) of abiraterone and enzalutamide. Surface under cumulative ranking curves (SUCRAs) and cumulative ranking probability plots based on the probability of developing cardiac disorders or hypertension were presented.
Results A total of 7103 patients from seven RCTs were included. Upon pairwise meta-analysis, abiraterone was associated with increased risks of any grade (RR = 1.34, 95% confidence interval (CI) = 1.05–1.73) and severe grade cardiac disorders (RR = 1.71, 95% CI = 1.16–2.53); enzalutamide was associated with increased risks of any grade (RR = 2.66, 95% CI = 1.93–3.66) and severe grade hypertension (RR = 2.79, 95% CI = 1.86–4.18). Based on the SUCRA rankings, abiraterone had a higher probability of cardiac disorders (84.84% for any grade and 85.12% for severe grade) than enzalutamide (62.83% for any grade and 50.76% for severe grade); whereas enzalutamide had a higher probability of hypertension (99.43% for any grade and 89.71% for severe grade) than abiraterone (49.08% for any grade and 49.37% for severe grade).
Conclusions Abiraterone and enzalutamide had different adverse effects on the cardiovascular system. We should take this into consideration when we are deciding on the choice of novel hormonal agents for patients with CRPC.
Introduction
Prostate cancer is the third commonest malignancy with more than 1.2 million new cases diagnosed in 2018 worldwide.1 Androgen deprivation therapy (ADT) was first reported in 1940 and it has revolutionized the management of metastatic prostate cancer.2 ADT is considered the backbone treatment for patients with metastatic prostate cancer. Unfortunately, about one-third of the patients would develop metastatic castration-resistant prostate cancer (CRPC) within 2 years.3 It is also not an uncommon practice to give primary ADT for patients with localized disease.4,5 Therefore, a rather distinct disease entity of nonmetastatic CRPC also exists in our clinical practice. Patients who develop CRPC will require additional treatments on top of conventional ADT.
There has been a big change in the treatment paradigm of advanced prostate cancer in recent years.6,7 In particular, novel hormonal agents have become an important treatment modality across various stages of prostate cancer. Abiraterone, an oral androgen synthesis inhibitor, and enzalutamide, a second-generation antiandrogen, have been approved for patients with CRPC. Both drugs were shown to be effective in improving survival outcomes, and they appeared to be well tolerated under clinical trial setting. They are also less toxic than chemotherapy, and a Canadian study has demonstrated a shift from chemotherapy toward novel hormonal agents as first-line treatment for metastatic CRPC.8
However, the use of hormonal therapy is not without risks. Androgen suppression may affect the cardiovascular system directly via endothelial dysfunction and indirectly via dysregulation of metabolic pathways.9,10 In clinical studies, conventional ADT has also been shown to increase risks of cardiovascular events such as acute myocardial infarction and stroke.11-14 As abiraterone and enzalutamide also act on the hormonal pathways, there is a concern whether they will lead to increased cardiovascular risk in long run. Such risk may be further accentuated by the continuation of conventional ADT throughout the treatment course.
A previous systematic review investigated the risk of cardiovascular toxicity of novel hormonal agents.15 Under the umbrella of novel hormonal agents, it was shown that the use of abiraterone or enzalutamide significantly increased the incidence of cardiovascular toxicity in patients with prostate cancer. However, there is lack of comparison between abiraterone and enzalutamide. In the PROSPER study investigating the use of enzalutamide in nonmetastatic CRPC, a clinical benefit in metastasis-free survival was demonstrated, but this was accompanied by a worrying 3% rate of adverse events leading to death, versus 1% in the placebo arm. While a direct comparative study between abiraterone and enzalutamide is lacking, an indirect comparison between the two drugs using network meta-analysis is possible. This is an important question that may carry significant implications in our clinical practice.
Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines.16 The study protocol was registered on PROSPERO (Registration No.: CRD42020140807).17
Search strategy and study selection
A comprehensive literature search was performed using keywords (MeSH terms and free text words) related to “abiraterone,” “enzalutamide,” “prostate cancer,” and “adverse events.” MEDLINE, EMBASE, and Cochrane library (CENTRAL and CDSR) were searched. The search was limited to include studies published since 1990. The search strategy was presented in Appendix 1. Additional references were sought from the reference lists of the included studies. The inclusion criteria were as follows: (1) phase II–IV randomized trial involving adult men with prostate cancer, (2) active intervention of either abiraterone or enzalutamide, (3) comparison between abiraterone and enzalutamide, or comparison with placebo, and (4) available data on safety outcome regarding cardiovascular events. Only full articles with English texts were included.
Data extraction and quality assessment
Two independent reviewers performed data extraction and quality assessment. Study information including the trial name, inclusion criteria, and intervention being given were recorded. The outcome measures included the incidence of (1) any grade cardiac disorders, (2) severe grade cardiac disorders, (3) any grade hypertension, and (4) severe grade hypertension. “Cardiac disorder” and “hypertension” were defined by the Common Terminology Criteria for Adverse Events.18 “Any grade” was defined as grade 1–5 adverse events. “Severe grade” was defined as grade 3–5 adverse events, i.e., life-threatening consequence and mortality. The detailed descriptions of the outcome measures were listed in Appendix 2. Furthermore, we also reported individual severe cardiac outcomes, such as atrial fibrillation, myocardial infarction, and cardiac failure. Quality assessment was performed using the risk of bias (ROB) assessment tool as recommended by the Cochrane Handbook for Systematic Reviews of Interventions.19 Any discrepancy between the two reviewers was resolved by discussion with a third reviewer.
Data synthesis and statistical analysis
In order to examine the risk ratios (RRs) of the novel hormonal agents (i.e., abiraterone or enzalutamide), the control arms of the included studies (i.e., placebo, prednisone, or prednisolone) were defined as the reference group for comparisons. Besides, we also examine the risk difference (RDs) between novel hormonal agents and control arms.
Pairwise meta-analysis
Pairwise meta-analysis was performed if there were more than one randomized trial reporting on the same outcome. The DerSimonian and Laird random effects model was used, assuming that a common intervention effect is relaxed, and that the effect sizes have a normal distribution.20 RRs and 95% confidence interval (CI) were used to indicate treatment effect. I 2 statistics was used to measure the proportion of total variation in study estimates attributed to heterogeneity, with an I 2 of >50% indicating substantial heterogeneity. Publication bias was presented by a funnel plot. No subgroup comparisons were performed as the number of studies included was too limited. Pairwise meta-analysis was performed using Review Manager Version 5.3.21
Network meta-analysis
Bayesian network meta-analysis was performed to compare the cardiovascular risks between abiraterone, enzalutamide, and placebo.22 Markov chain Monte Carlo was performed with 50,000 simulations across three chains (150,000 simulations in total) with 5000 burn-in steps.23 RRs and 95% credible intervals (CrI), i.e. 2.5 and 97.5 percentiles from simulation results, were presented to indicate the treatment effect. Surface under cumulative ranking curves (SUCRAs) and cumulative ranking probability plots based on the probability of developing cardiac disorders and hypertension were presented.24 Network meta-analysis was performed using WinBUGS version 1.4.3.
Results
Literature search
A total of 1470 studies were identified from our literature search. Among them, 410 were duplicates and were removed. After initial screening, 1047 were further removed, resulting in 13 studies for full text review. At the end of the process, seven studies met our inclusion criteria and remained for qualitative synthesis and quantitative meta-analysis. The PRIMSA flow diagram is presented in Appendix 3.
Study characteristics and quality evaluation
The study characteristics of the seven included studies are presented in Appendix 4.25-31 All studies were phase II or III trials that were completed between 2012 and 2015. Abiraterone was used as the active intervention in four randomized controlled trials (RCTs), with prednisone or prednisolone being the therapy for the control group. For the other three RCTs, patients were randomized to receive either enzalutamide or placebo. All subjects in the seven RCTs had received ADT before randomization and were continued throughout the trials. Six RCTs recruited patients with metastatic CRPC, but one RCT comparing between enzalutamide and placebo involved patients without metastatic disease. The median follow-up durations ranged from 3.9 to 22.2 months. The ROB assessment is presented in Appendix 5.
Pairwise meta-analysis
A total of 7103 patients from seven RCTs were included. Among them, 1633 were treated with abiraterone and 2601 were treated with enzalutamide; 2869 patients were treated with placebo, prednisone, or prednisolone in the control arms.
Cardiac disorders
Overall, the use of novel hormonal agents (abiraterone or enzalutamide) increased the risk of any grade cardiac disorders by 33% (RR = 1.33, 95% CI = 1.07–1.65, I 2 = 45%, p = 0.01) and severe grade cardiac disorders by 51% (RR = 1.51, 95% CI = 1.03–2.22, I 2 = 38%, p = 0.03). For patients who received abiraterone, there were increased risks of any grade cardiac disorder (RR = 1.34, 95% CI = 1.05–1.73, I 2 = 26%, p = 0.02) and severe grade cardiac order (RR = 1.71, 95% CI = 1.16–2.53, I 2 = 0%, p = 0.007). On the other hand, there was no increased risk of any grade cardiac disorder (RR = 1.28, 95% CI = 0.82–2.01, I 2 = 69%, p = 0.27) and severe grade cardiac disorder (RR for severe events = 1.24, 95% CI = 0.56–2.75, I 2 = 69%, p = 0.60) for patients who received enzalutamide. The results are summarized in Fig. 1 and consistent results were noted for RDs in Appendix 6. On the other hand, no statistical effects were presented on individual cardiac events (atrial fibrillation, myocardial infarction, and cardiac failure) among subjects with novel hormonal agents (Appendix 7).
Figure 1. Results from pairwise meta-analysis on cardiac disorders. (a) Any grade cardiac disorders. (b) High-grade cardiac disorders.
Hypertension
Overall, the use of novel hormonal agents (abiraterone or enzalutamide) increased the risk of any grade hypertension by 80% (RR = 1.80, 95% CI = 1.33–2.43, I 2 = 70%, p < 0.001) and severe grade hypertension by 82% (RR = 1.82, 95% CI = 1.17–2.83, I 2 = 48%, p = 0.008). For patients who received abiraterone, there were increased risks of any grade hypertension (RR = 1.46, 95% CI = 1.20–1.78, I 2 = 70%, p < 0.001), but not severe grade hypertension (RR = 1.29, 95% CI = 0.84–1.98, I 2 = 0%, p = 0.25). On the other hand, the use of enzalutamide was associated with increased risk of both any grade hypertension (RR = 2.66, 95% CI = 1.93–3.66, I 2 = 35%, p < 0.001) and severe grade hypertension (RR = 2.79, 95% CI = 1.86–4.18, I 2 = 0%, p < 0.001). The results are summarized in Fig. 2 and consistent results were noted for RDs in Appendix 6.
Figure 2. Results from pairwise meta-analysis on hypertension. (a) Any grade hypertension. (b) High-grade hypertension.
Network meta-analysis
An indirect treatment comparison, between abiraterone, enzalutamide, and the control arm, was performed using network meta-analysis. RRs and SUCRAs from network meta-analysis are summarized in Table 1 (for cardiac disorders) and Table 2 (for hypertension). Besides, consistent results were noted for RDs in Appendix 6 and effects on individual cardiac disorder were summarized in Appendix 7. The cumulative ranking probability plots are presented in Fig. 3.
Table 1. Risk ratios of cardiac disorders from network meta analysis.
Table 2. Risk ratios of cardiac disorders from network meta analysis.
Figure 3. Cumulative ranking probability plots on impact of cardiac disorders and hypertension.
Cardiac disorders
When compared to the placebo group, the RR of any grade cardiac disorders was significantly higher among those who received abiraterone (RR = 1.32, 95% CrI = 1.08–1.62), but not among those who received enzalutamide (RR for any grade = 1.22, 95% CrI = 0.97–1.54). The RRs of severe grade cardiac disorders were 1.84 for abiraterone and 1.33 for enzalutamide, but they did not reach statistical significance. Based on the SUCRA rankings, abiraterone had the highest probability of cardiac disorders (84.84% for any grade, 85.12% for severe grade), followed by enzalutamide (62.83% for any grade, 50.76% for severe grade) and placebo group (2.33% for any grade, 14.12% for severe grade). Although atrial fibrillation was known to occur with abiraterone due to mineralocorticoid excess, no statistical difference was presented between Abi and Enza from network meta-analysis. On the other hand, patients on enzalutamide had a higher probability of developing myocardial infarction but without statistically significant differences in MI risk among abiraterone, enzalutamide, and control arm.
Hypertension
When compared to the placebo group, the RR of any grade hypertension was significantly higher among those who received enzalutamide (RR = 2.72, 95% CrI = 1.85–3.84), but not among those who received abiraterone (RR = 1.44, 95% CrI = 0.97–1.98). The RRs of severe grade cardiac disorders were 2.79 for enzalutamide and 1.47 for enzalutamide, but they did not reach statistical significance. Interestingly, enzalutamide had a higher risk of any grade hypertension than abiraterone (RR = 1.88, 95% CrI = 1.16–3.13); the RR of severe grade hypertension was 1.89 for enzalutamide but it did not reach statistical significance. Based on the SUCRA rankings, enzalutamide had the highest probability of hypertension (99.43% for any grade, 89.71% for severe grade), followed by abiraterone (49.08% for any grade, 49.37% for severe grade) and placebo group (1.01% for any grade, 10.92% for severe grade).
Discussion
The effects of androgen suppression in prostate cancer were first reported by Huggins et al.2 ADT had been shown to improve quality of life, reduction of disease-associated morbidity, and possibly survival.32 Therefore, ADT has been the cornerstone treatment for patients with advanced prostate cancer. However, the use of ADT is associated with increased risk of cardiovascular events.9 There are several modalities of ADT, with luteinizing hormone-releasing hormone antagonists having the best cardiovascular profile.33 In recent years, the introduction of novel hormonal agents had led to a changing treatment paradigm in patients with metastatic prostate cancer. Given that these drugs also act on the hormonal pathways, there is a reasonable concern that they may further increase the risk of cardiovascular events. While prostate cancer tends to occur in elderly men with comorbidities,34,35 these are also the patients who are vulnerable to developing cardiovascular events. It is important to investigate thoroughly about the cardiovascular risk of novel hormonal agents.
Although there are a number of randomized trials investigating the efficacy of novel hormonal agents, there is no high-quality study directly comparing between abiraterone and enzalutamide. In the meta-analysis by Iacovelli et al.,15 it was found that both abiraterone and enzalutamide were associated with increased risk of cardiovascular toxicity, however, only a comparison with the placebo group was made and we do not know how the two drugs were compared. A properly conducted indirect comparison between abiraterone and enzalutamide becomes important to answer our clinical question. A network meta-analysis is a meta-analysis in which multiple treatments are being compared using both direct comparisons of interventions within RCTs and indirect comparisons across trials based on a common comparator.36,37 Such methodology has been widely used in various fields including prostate cancer;38,39 this is also the methodology that we have used in our study.
We have included a total of 7103 patients from seven RCTs in our study. Most RCTs are considered high-quality studies with low ROB. There are two most striking findings from our pairwise meta-analysis. First, abiraterone was associated with increased risk of any grade and severe grade cardiac conditions, but not with severe grade hypertension. Second, enzalutamide was associated with increased risk of any grade and severe grade hypertension, but not with any grade or severe grade cardiac disorders. Severe grade adverse events, by definition, are potentially life threatening (Grade 4) and may lead to mortality (Grade 5). This information will be particularly important when we manage CRPC patients with underlying cardiac disorders and uncontrolled hypertension. However, due to the limited number of studies being included, we are not able to perform further subgroup analysis based on the patients’ cardiovascular characteristics.
CYP17 is the pivotal enzyme for the production of androgens. It is responsible for the conversion of pregnenolone and progesterone to dehydroepiandrosterone and androstenedione, which are the direct precursors of testosterone and dihydrotestosterone.40 Abiraterone is a CYP17 inhibitor, and the primary effect is the complete blockade of androgen production. Suppression of androgens may lead to (1) inactivation of hormone-sensitive lipase leading to loss in muscle mass and increase in fat composition,41 and (2) insulin resistance predisposing the development of metabolic syndrome.42 These are the metabolic pathways that may accelerate the development of atherosclerosis and the risk of cardiovascular events. Previous studies have shown that CYP17 polymorphisms were associated with coronary artery disease;43,44 this is compatible with the results of our study. On the other hand, the inhibition of CYP17 may trigger the feedback mechanism of the axis, resulting in excess of mineralocorticoid. An excess of mineralocorticoid should lead to hypertension, but the results of our study are contrary to what we have expected. Given that concomitant use of steroid is a general recommendation upon initiation of abiraterone, we believe that this potential side effect of hypertension had already been largely counteracted in a prophylactic manner.
Enzalutamide acts on the androgen receptor pathway by preventing ligand binding, by blocking androgen receptor nuclear translocation and by inhibiting DNA transactivation, and ultimately abrogating androgen receptor-dependent gene expression.45-47 Instead of suppressing the androgen level directly, enzalutamide has the capacity to overcome androgen receptor overexpression, which is an adaptive mechanism in the development of CRPC.46 This fundamental difference may be the reason why we did not detect any significant increased risk of cardiac disorders after enzalutamide. On the other hand, androgen receptor plays an important role in endothelial function.48 Activation of androgen receptor has been shown to stimulate endothelial cell proliferation, which promotes the repair of endothelial cell injury and prevents endothelial dysfunction.49 The early manifestation of endothelial dysfunction is an impairment of smooth muscle relaxation in the blood vessels, resulting in the development of hypertension. We postulate that enzalutamide, by its direct action at the receptor level, may lead to substantial endothelial dysfunction and an increased risk of hypertension as demonstrated by our study.
To the best of our knowledge, this is the first network meta-analysis to compare between abiraterone and enzalutamide, in patients with CRPC with special focus in cardiovascular adverse events. We found that abiraterone and enzalutamide carry different patterns of cardiovascular toxicity, and this may have important implications in our clinical practice. However, there are several limitations in our study. First, all patients in the abiraterone group had concomitant use of steroid, and this may mask the true adverse effects of abiraterone on the cardiovascular system. However, this is perhaps more clinically applicable as it is very unlikely for clinicians to start abiraterone without steroid. Second, we wish to investigate which group of patients (e.g., based on underlying cardiovascular conditions) is more prone to developing cardiac disorders and hypertension after the use of novel hormonal agents, however, such subgroup analysis is not possible given the small number of studies being included. Third, in network meta-analysis, it is extremely crucial to have a similar control group to allow such indirect comparison. Although we only included RCTs in our network analysis where strict inclusion and exclusion criteria were followed, and we only included patients with CRPC, the homogeneity of the control groups could not be ensured.
Conclusions
Our pairwise and network meta-analyses showed that abiraterone and enzalutamide had different adverse effects on the cardiovascular system. Abiraterone increased the risk of cardiac orders and enzalutamide increased the risk of hypertension. We should take this into consideration when we are managing patients with CRPC.
Acknowledgments - This study was supported by grants from the Kaohsiung Municipal Ta-Tung Hospital (KMTTH 107-018).
Author contributions HYL: protocol development and manuscript writing; HLC: protocol development, data analysis, and paper writing; JYCT: data interpretation and paper writing TCC: protocol/project development; SYH and HYT: data extraction; WHH and YSJ: data interpretation; HM Cheng and HM Chang: project development and paper writing.
Compliance with ethical standards
Conflict of interest - The authors declare that they have no conflict of interest.
Publisher’s note - Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors: Hsiang Ying Lee,1,2,3 Hsiao-Ling Chen,4 Jeremy Yuen-Chun Teoh,5 Tun-Chieh Chen,6 Shao-Yuan Hao,4 Hsin-Yi Tsai,4 Wei-Hsuan Huang,4 Yung-Shun Juan,1,3 Hao-Min Cheng,7,8,9 Hsiu-Mei Chang4
1. Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
2. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
4. Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
5. S.H. Ho Urology Centre, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
6. Division of Infectious Diseases, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
7. Center for Evidence-based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
8. Institute of Public Health, National Yang-Ming University Hospital, Taipei, Taiwan
9. Department of Medicine, National Yang-Ming University, Taipei, Taiwan
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Read an Editorial by Stephen J. Freedland, MD: Adverse Effects on the Cardiovascular System in Men with metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide - Editorial