Adverse Events and Androgen Receptor Signaling Inhibitors in the Treatment of Prostate Cancer: A Systematic Review and Multivariate Network Meta-analysis

Cao, Brent; Kim, Melissa; Reizine, Natalie; Moreira, Daniel

doi:10.1016/j.euo.2023.01.001

Cited by 10 publications

(6 citation statements)

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“…Studies revealed that AR axis-targeted therapies had different profiles of CV AEs ( 34 – 38 ). A meta-analysis of three landmark studies conducted in patients with nonmetastatic castration-resistant PCa (nmCRPC) showed that apalutamide, darolutamide, and enzalutamide were associated with significantly increased risks of hypertension (relative risks [RRs] 1.213, 1.452, and 2.150, respectively) and CV events (RRs 4.466, 2.710, and 2.125, respectively) compared with placebo ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

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Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Poon,

Tan,

Chan

et al. 2024

Front. Oncol.

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BackgroundAndrogen deprivation therapy (ADT) is the foundational treatment for metastatic prostate cancer (PCa). Androgen receptor (AR) axis-targeted therapies are a new standard of care for advanced PCa. Although these agents have significantly improved patient survival, the suppression of testosterone is associated with an increased risk of cardiometabolic syndrome. This highlights the urgency of multidisciplinary efforts to address the cardiometabolic risk of anticancer treatment in men with PCa.MethodsTwo professional organizations invited five urologists, five clinical oncologists, and two cardiologists to form a consensus panel. They reviewed the relevant literature obtained by searching PubMed for the publication period from April 2013 to April 2023, to address three discussion areas: (i) baseline assessment and screening for risk factors in PCa patients before the initiation of ADT and AR axis-targeted therapies; (ii) follow-up and management of cardiometabolic complications; and (iii) selection of ADT agents among high-risk patients. The panel convened four meetings to discuss and draft consensus statements using a modified Delphi method. Each drafted statement was anonymously voted on by every panelist.ResultsThe panel reached a consensus on 18 statements based on recent evidence and expert insights.ConclusionThese consensus statements serve as a practical recommendation for clinicians in Hong Kong, and possibly the Asia-Pacific region, in the management of cardiometabolic toxicities of ADT or AR axis-targeted therapies in men with PCa.

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Section: Resultsmentioning

confidence: 99%

“…In a recent systematic review and meta-analysis of RCTs that included patients who received AR axis-targeted therapies for nmCRPC, mCRPC, and mHSPC, enzalutamide was ranked the most toxic regarding hypertension in the settings of nmCRPC and mCRPC ( 38 ).…”

Section: Resultsmentioning

confidence: 99%

Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Poon,

Tan,

Chan

et al. 2024

Front. Oncol.

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“…In recording adverse events caused by the four drugs during treatment, it was found that the incidence of adverse events caused by the four drugs was not significantly different overall and only for single adverse events. The results of a meta-analysis showed that among second-generation ARSIs, enzalutamide was associated with a significantly higher risk of increased blood pressure (SUCRA 0%) and headache (SUCRA 3%) in patients with mHSPC ( 31 ). Additionally, Zhang X and colleagues discovered that second-generation ARSIs were more effective than bicalutamide in prolonging both patient’s survival and disease progression, without a notable increase in the occurrence of adverse events ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative effectiveness of multiple androgen receptor signaling inhibitor medicines with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a study in the real world

Lu,

Jiang,

Yang

et al. 2024

Front. Oncol.

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BackgroundThe current treatment strategy for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) is the combination of Androgen Receptor Signaling Inhibitors (ARSIs) medicines with androgen deprivation therapy (ADT). However, there is a lack of real-world data comparing the efficacy of different ARSI pharmaceuticals. Therefore, the objective of this study was to compare the effectiveness and safety of bicalutamide, abiraterone, enzalutamide, and apalutamide in combination with ADT for patients with mHSPC.MethodsWe retrospectively analyzed 82 patients diagnosed with mHSPC, including 18 patients treated with abiraterone acetate with prednisone, 21 patients with enzalutamide, 20 patients with apalutamide, and 23 patients with bicalutamide. We evaluated PSA progression-free survival (PSA-PFS), imaging progression-free survival (r PFS), castration resistance progression-free survival (CRPC-PFS), and overall survival (OS) using Kaplan-Meier survival analyses. Additionally, we explored relevant factors affecting prognosis through univariate and multivariate Cox risk-proportionality models. PSA response rates at 3, 6, and 12 months, nadir PSA levels (nPSA), and time to nadir (TTN) in different medication subgroups after treatment were documented, and we used one-way ANOVA to determine the effect of these measures on patient prognosis.ResultsIn comparison with bicalutamide, both enzalutamide and apalutamide have shown significant advantages in delaying disease progression among mHSPC patients. Specifically, enzalutamide has been found to significantly prolong PSA-PFS (HR 2.244; 95% CI 1.366-3.685, p=0.001), rPFS (HR 2.539; 95% CI 1.181-5.461; p= 0.007), CRPC-PFS (HR 2.131; 95% CI 1.295-3.506; p= 0.003), and OS (HR 2.06; 95% CI 1.183-3.585; P=0.005). Similarly, apalutamide has significantly extended PSA-PFS (HR 5.071; 95% CI 1.711-15.032; P= 0.003) and CRPC-PFS (HR 6.724; 95% CI 1.976-22.878; P=0.002) among patients. On the other hand, the use of abiraterone in combination with ADT did not demonstrate a significant advantage in delaying diseases progression when compared with the other three agents in mHSPC patients. There were no significant differences in overall adverse event rates among the four pharmaceuticals in terms of safety. Additionally, the observation of PSA kinetics revealed that enzalutamide, apalutamide, and abiraterone acetate had a significant advantage in achieving deep PSA response (PSA ≤ 0.2 ng/ml) compared with bicalutamide (p=0.007 at 12 months). Enzalutamide and apalutamide exhibited preeminence efficacy, with no substantial difference observed between the two medications.ConclusionsAbiraterone, enzalutamide, and apalutamide were found to significantly reduce and stabilize PSA levels in mHSPC patients more quickly and thoroughly than bicalutamide. Furthermore, enzalutamide and apalutamide were found to significantly prolong survival and delay disease progression in mHSPC patients compared with bicalutamide. It should be noted that abiraterone did not demonstrate a significant advantage in delaying disease compared with enzalutamide and apalutamide. After conducting drug toxicity analyses, it was determined that there were no significant differences among the four drugs.

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“…Previous meta-analyses of randomized clinical trials in this setting have largely focused on oncological end points, rather than adverse events (AEs) including CV events in sufficient detail . Furthermore, the data do not currently reflect the nature of contemporary treatments in modern clinical trials, where ARSI agents are increasingly used in earlier stages of disease .…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

El-Taji,

Taktak,

Jones

et al. 2024

JAMA Oncol

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ImportanceCardiovascular (CV) events remain a substantial cause of mortality among men with advanced and metastatic prostate cancer (PCa). The introduction of novel androgen receptor signaling inhibitors (ARSI) has transformed the treatment landscape of PCa in recent years; however, their associated CV toxic effects remains unclear.ObjectiveTo assess the incidence of CV events with addition of ARSI to standard of care (SOC) in locally advanced (M0) and metastatic (M1) PCa.Data SourcesSystematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed from inception up to May 2023.Study SelectionRandomized clinical trials of ARSI agents (abiraterone, apalutamide, darolutamide, enzalutamide) that reported CV events among individuals with M0 and M1, hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC).Data Extraction and SynthesisA systematic review was performed in accordance with PRISMA guidance. Two authors screened and independently evaluated studies eligible for inclusion. Data extraction and bias assessment was subsequently performed.Main Outcomes and MeasuresA random-effects meta-analysis was performed to estimate risk ratios for the incidence of all grade and grade 3 or higher CV events (primary outcomes), in addition to hypertension, acute coronary syndrome (ACS), cardiac dysrhythmia, CV death, cerebrovascular event, and venous thromboembolism (secondary outcomes). Sources of heterogeneity were explored using meta-regression.ResultsThere were 24 studies (n = 22 166 patients; median age range, 63-77 years; median follow-up time range, 3.9-96 months) eligible for inclusion. ARSI therapy was associated with increased risk of all grade CV event (risk ratio [RR], 1.75; 95% CI, 1.50-2.04; P &lt; .001) and grade 3 or higher CV events (RR, 2.10; 95%, 1.72-2.55; P &lt; .001). ARSI therapy also was associated with increased risk for grade 3 or higher events for hypertension (RR, 2.25; 95% CI, 1.74-2.90; P &lt; .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P &lt; .01), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P &lt; .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P &lt; .001) and for CV-related death (RR, 2.02; 95% CI, 1.32-3.10; P = .001). Subgroup analysis demonstrated increased risk of all CV events across the disease spectrum (M0 HSPC: RR, 2.26; 95% CI, 1.36-3.75; P = .002; M1 HSPC: RR, 1.85; 95% CI, 1.47-2.31; P &lt; .001; M0 CRPC: RR, 1.79; 95% CI, 1.13-2.81; P = .01; M1 CRPC: RR, 1.46; 95% CI, 1.16-1.83; P = .001).Conclusions and RelevanceThis systematic review and meta-analysis found that the addition of ARSIs to traditional ADT was associated with increased risk of CV events across the prostate cancer disease spectrum. These results suggest that patients with prostate cancer should be advised about and monitored for the potential of increased risk of CV events with initiation of ARSI therapy alongside conventional hormonal therapy.

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Adverse Events and Androgen Receptor Signaling Inhibitors in the Treatment of Prostate Cancer: A Systematic Review and Multivariate Network Meta-analysis

Cited by 10 publications

References 61 publications

Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology

Comparative effectiveness of multiple androgen receptor signaling inhibitor medicines with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a study in the real world

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

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