Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Omar El-Taji; Samih Taktak; Craig Jones; Mick Brown; Noel Clarke; Ashwin Sachdeva

doi:10.1001/jamaoncol.2024.1549

. 2024 Jun 6;10(7):874–884. doi: 10.1001/jamaoncol.2024.1549

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

A Systematic Review and Meta-Analysis

Omar El-Taji ^1,^2,³, Samih Taktak ⁴, Craig Jones ^1,^2,³, Mick Brown ¹, Noel Clarke ^1,^2,³, Ashwin Sachdeva ^1,^2,^✉

¹Genito Urinary Cancer Research Group, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Department of Surgery, The Christie NHS Foundation Trust, Manchester, United Kingdom

³Department of Urology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester, United Kingdom

⁴Wirral University Teaching Hospitals NHS Foundation Trust, Wirral, United Kingdom

Accepted for Publication: December 29, 2023.

Published Online: June 6, 2024. doi:10.1001/jamaoncol.2024.1549

^✉

Corresponding Author: Ashwin Sachdeva, MBBS, PhD, Genito Urinary Cancer Research Group, Division of Cancer Sciences, University of Manchester, 555 Wilmslow Rd, Manchester M20 4GJ, United Kingdom (ashwin.sachdeva@manchester.ac.uk).

Author Contributions: Dr Sachdeva had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: El-Taji, Clarke, Sachdeva.

Drafting of the manuscript: El-Taji, Brown, Clarke, Sachdeva.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: El-Taji, Taktak.

Obtained funding: Clarke, Sachdeva.

Administrative, technical, or material support: Taktak, Clarke, Sachdeva.

Supervision: Brown, Clarke, Sachdeva.

Conflict of Interest Disclosures: Dr El-Taji reported personal fees from Bayer outside the submitted work. Dr Jones reported personal fees from Janssen and Bayer outside the submitted work. Dr Clarke has received institutional consultancy or advisory fees from Astellas Pharma, Bayer, Ferring, Janssen-Cilag, and Sanofi; honoraria from Astellas Pharma, Bayer, Janssen-Cilag, and Sanofi; speaker bureau fees from Astellas Pharma, AstraZeneca, and Janssen-Cilag; and travel and accommodation expenses from Astellas Pharma, AstraZeneca, Bayer, Ferring, Ipsen, Janssen-Cilag, and Sanofi. Dr Sachdeva reported nonfinancial support from AIRAMatrix (travel costs) outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported, in part, by a Prostate Cancer Foundation-John Black Charitable Foundation Young Investigator Award to Dr Sachdeva, the Belfast–Manchester Movember Prostate Cancer UK Centre of Excellence FASTMAN program, and by Peel holdings through the Christie NHS Charitable Trust.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: The authors would like to thank Peter Godolphin, PhD, at Medical Research Council Clinical Trials Unit, University College London, for statistical advice. He was not compensated.

^✉

Corresponding author.

PMCID: PMC11157448 PMID: 38842801

Key Points

Question

Are androgen receptor signaling inhibitors associated with increased risk of cardiovascular events in men with advanced and metastatic prostate cancer?

Findings

In this systematic review and meta-analysis of 24 randomized clinical trials involving 22 166 patients, the addition of androgen receptor signaling inhibitors alongside standard androgen deprivation therapy was associated with significantly increased risk of men experiencing cardiovascular events.

Meaning

These results suggest that patients with prostate cancer should be counselled and monitored for an increased risk of cardiovascular events with initiation of androgen receptor signaling inhibitors alongside conventional hormonal therapy.

This systematic review and meta-analysis investigates the incidence of cardiovascular events with addition of novel androgen receptor signaling inhibitors (ARSI) to standard of care in locally advanced and metastatic prostate cancer.

Abstract

Importance

Cardiovascular (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.

Objective

To assess the incidence of CV events with addition of ARSI to standard of care (SOC) in locally advanced (M0) and metastatic (M1) PCa.

Data Sources

Systematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed from inception up to May 2023.

Study Selection

Randomized 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 Synthesis

A 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 Measures

A 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.

Results

There 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 < .001) and grade 3 or higher CV events (RR, 2.10; 95%, 1.72-2.55; P < .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 < .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P < .01), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P < .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P < .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 < .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 Relevance

This 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.

Introduction

Androgen deprivation therapy (ADT) is a key component in standard of care (SOC) for men with locally advanced or metastatic prostate cancer (PCa). More recently, the addition of novel androgen receptor signaling inhibitors (ARSI) to ADT used in combination with local site radiotherapy (RT), when appropriate, has resulted in substantial benefits in survival in locally advanced (M0) and metastatic (M1) PCa.^1,2,3 Since 2012, more than half a million patients have been prescribed ARSI agents.⁴ It is therefore essential to understand whether improvement in survival attributed to intensified treatment is also associated with emergence of serious adverse effects.

Cardiovascular (CV) events cause substantial morbidity and mortality among men with PCa.^5,6 Several factors contribute to this increased risk of CV events, of which, alterations in lipid profile, altered body composition and preexisting CV disease are most well defined.^7,8,9,10 ADT monotherapy has known adverse effects, of which CV toxic effects are most critical,¹¹ though current evidence linking ADT use to CV toxic effects is conflicting.^12,13 Given that addition of ARSI agents to traditional ADT has resulted in improved survival, patients with PCa using combination therapies are exposed to an increased period of intense androgen deprivation. Therefore, there is a greater need to better understand the risk of CV toxic effects with combination therapy.

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.^{14,15,16,17,18,19} 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.^20,21,22 There is therefore need for a contemporary meta-analysis that synthesizes the most recent clinical trial data on the CV outcomes of combination ARSI therapy across the spectrum of PCa to provide an evidence-based framework to inform clinical decision-making.

We therefore evaluated the risk of CV events with ADT intensification with ARSIs among patients with high-risk nonmetastatic hormone-sensitive prostate cancer (M0 HSPC), metastatic hormone-sensitive prostate cancer (M1 HSPC), nonmetastatic castration-resistant prostate cancer (M0 CRPC), and metastatic castration-resistant prostate cancer (M1 CRPC).

Methods

Protocol and Registration

This systematic review and meta-analysis was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (Supplement 1).²³ A protocol for this study was registered and published in advance on the International Prospective Register of Systematic Reviews (PROSPERO Registration ID CRD 408514).

Search Strategy

Systematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed to identify randomized clinical trials (RCTs) assessing ARSI agents in the treatment of PCa, from inception through to May 2023 (eTable 1 in Supplement 1). Two authors individually performed initial screening (O.E., S.T.) and independently evaluated studies eligible for inclusion. Any disagreements were resolved by consensus in discussion with a third author (A.S.).

Inclusion and Exclusion Criteria

Eligible RCTs including patients with M0 HSPC, M1 HSPC, M0 CRPC and M1 CRPC treated with novel (abiraterone acetate) and second-generation (enzalutamide, apalutamide, darolutamide) ARSIs and either a placebo or SOC as per trial protocol. All nonrandomized studies and those including an ARSI agent in the control group were excluded. Where multiple published reports were available for the same trial, the most recent and updated version was included in the final analysis. Prior and concurrent docetaxel use was considered acceptable for inclusion.

Outcome Measures

The primary outcomes were all grade and grade 3 or higher composite CV events. To classify as a composite event, a study was required to report on more than 1 CV condition. Secondary outcomes included clinically relevant conditions subclassified within the CV disease spectrum, including the presence of grade 3 or higher AEs for hypertension, acute coronary syndrome (ACS), cardiac dysrhythmia, cerebrovascular event, and venous thromboembolism and CV-related death. These terms were defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and confirmed by consulting the European guidelines for CV disease, as the onset of any adverse CV event (eTable 2 in Supplement 1).^24,25 AEs were cross-referenced with ClinicalTrials.gov when not reported.

Data Extraction and Quality Assessment

Baseline characteristics, interventions, and follow-up duration as well as primary and secondary outcome data were independently extracted by authors (O.E., S.T.). Authors were contacted in the case of missing data. Assessment of study quality and risk of bias was performed independently by the same 2 authors using the Cochrane Handbook for Systematic Reviews of Interventions Risk of Bias tool (RoB version 2.0), and results were visualized using the Robvis package²⁶ in R version 4.1.2 (R Project for Statistical Computing). Assessment of small study effects was visualized using funnel plots and quantified using the Egger test for funnel plot asymmetry.²⁷ Quality of evidence and strength of recommendation was assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.²⁸

Statistical Analysis

A pairwise meta-analysis was performed using the meta package in R. Dichotomous data were analyzed using the Mantel-Haenszel–weighted random-effects model with the restricted maximum likelihood estimator of τ², regardless of calculated heterogeneity, and expressed as a risk ratio (RR) with 95% CI. Statistical heterogeneity was quantified using Cochran Q test and prediction intervals with inconsistency between studies measured using the I² statistic. Statistical analyses used a 2-sided method: P < .05 was considered statistically significant.

Subgroup and Sensitivity Analysis

A preplanned subgroup analysis based on disease state and type of ARSI treatment was conducted. Sensitivity analyses were performed to investigate the potential effects of uncertainties related to evidence selection. Weighted meta-regression analysis with a random-effects model was performed to quantify the potential moderating influence of participant and trial characteristics. We analyzed the association of age, ECOG performance status, follow-up duration, combination ARSI treatment, and prior or protocol docetaxel with the estimated log RR of CV events. Restricted maximum likelihood with Hartung and Knapp adjustment was used to obtain the F test statistic and P value.

Results

Studies Evaluated

Data from 24 eligible RCTs (n = 22 166) were included (Figure 1); M0 HSPC (3 RCTs, n = 2171),^1,29 M1 HSPC (9 RCTs, n = 8994),^{2,30,31,32,33,34,35,36} M0 CRPC (3 RCTs, n = 4256),^37,38,39 M1 CRPC (9 RCTs, n = 6745).^{40,41,42,43,44,45,46,47,48} One study had patients spanning different disease states, so these populations were split for analysis according to their separate publications.^45,49 The multiarm STAMPEDE trial presented data from 4 groups in 2 publications; these studies were considered separately given their different disease populations and control groups.^1,2 The median follow-up ranged from 3.9 to 96 months, and median age ranged from 63 to 77 years (Table; eTable 3 in Supplement 1). CV-related AEs were reported using CTCAE criteria for all but 1 study which did not specify the terminology criteria used.⁴²

Table. Characteristics of Included Studies.

Study and phase	Year	No. of patients, (ITT)		Treatment		Age, median (range), y		Median follow-up, mo	Grade 1-5 CV events (%)		Grade ≥3 CV events (%)
Study and phase	Year	Intervention	Control	Intervention	Control	Intervention	Control	Median follow-up, mo	Intervention	Control	Intervention	Control
M0 HSPC
STAMPEDE M0 (Comparison AG)¹ phase 3	2022	459	455	Abiraterone acetate + prednisolone + ADT	Placebo + ADT	68 (44-84)	67 (48-83)	72.0	155 (34.3)	90 (19.8)	31 (6.9)	11 (2.41)
STAMPEDE M0 (Comparison AJ)¹ phase 3	2022	527	533	Abiraterone acetate + prednisolone + Enza + ADT	Placebo + ADT	68 (46-86)	69 (64-73)	60.0	303 (59.0)	108 (20.3)	82 (15.9)	19 (3.6)
Spetsieris et al²⁹ phase 2	2021	99	98	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	65 (44-80)	65 (42-85)	64.4	NR	NR	NR	NR
M1 HSPC
STAMPEDE M1 (Comparison AJ)² phase 3	2023	462	454	Abiraterone acetate + prednisolone + enzalutamide + ADT	Placebo + prednisolone + ADT	69 (48-84)	68 (37-83)	72.0	347 (77.9)	121 (26.7)	109 (24.5)	29 (6.4)
STAMPEDE M1 (Comparison AG)² phase 3	2023	501	502	Abiraterone acetate + prednisolone + ADT	Placebo + ADT	67 (42-85)	67 (39-84)	96.0	290 (58.2)	123 (24.5)	60 (12.0)	18 (3.6)
ENZAMET³⁰ phase 3	2023	563	562	Enzalutamide + ADT	ADT + NSAA	69 (IQR, 63-74)	69 (IQR, 64-75)	68.0	301 (53.5)	175 (31.4)	116 (20.6)	70 (12.5)
ARCHES³¹ phase 3	2022	574	576	Enzalutamide + ADT	ADT + Placebo	70 (46-92)	70 (42-92)	44.6	144 (25.2)	69 (12.0)	57 (9.9)	39 (6.8)
ARASENS³² phase 3	2022	651	654	Darolutamide + docetaxel +ADT	Placebo + docetaxel + ADT	67 (41-89)	67 (42-86)	43.7	177 (27.0)	147 (22.6)	NR	NR
PEACE-1³³ phase 3	2022	583	589	Abiraterone acetate + prednisolone + ADT ± docetaxel ± RTx	Placebo + ADT ± docetaxel ± RTx	67 (37-94)	66 (43-87)	42.0	NR	NR	NR	NR
TITAN³⁴ phase 3	2021	525	527	Apalutamide + ADT	Placebo + ADT	68 (45-94)	69 (43-90)	44.0	152 (29.0)	107 (20.3)	72 (13.7)	55 (10.4)
LATITUDE³⁵ phase 3	2019	597	602	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	66 (8.5)^a	67 (8.7)^a	51.8	339 (56.8)	201 (33.4)	160 (26.8)	80 (13.2)
Vaishampayan et al³⁶ phase 2	2021	36	35	Enzalutamide + ADT	Bicalutamide + ADT	66 (54-86)	63 (51-84)	39.0	NR	NR	3 (8.6)	1 (2.9)
M0 CRPC
SPARTAN³⁷ phase 3	2021	806	401	Apalutamide + ADT	Placebo + ADT	74 (48-94)	74 (52-97)	52.0	NR	NR	172 (21.4)	59 (14.8)
PROSPER³⁸ phase 3	2020	933	468	Enzalutamide + ADT	Placebo + ADT	74 (50-95)	73 (53-92)	48.0	227 (24.4)	50 (10.8)	NR	NR
ARAMIS³⁹ phase 3	2020	955	554	Darolutamide+ ADT	Placebo + ADT	74 (48-95)	74 (50-92)	17.9	219 (22.9)	89 (16.1)	92 (9.6)	28 (5.1)
STRIVE M0⁴⁹ phase 3	2022	70	69	Enzalutamide + ADT	Bicalutamide + ADT	73.5 (50-92)	77 (58-91)	17.0	NR	NR	NR	NR
M1 CRPC
PREVAIL Asia⁴⁰ phase 3	2022	198	190	Enzalutamide + ADT	Placebo + ADT	71 (51-89)	71 (50-88)	60.0	31 (15.7)	8 (4.2)	NR	NR
PREVAIL⁴¹ phase 3	2020	872	845	Enzalutamide + ADT	Placebo + ADT	71 (43-93)	71 (42-93)	69.0	NR	NR	155 (17.8)	54 (6.4)
ABI-PRO-3002⁴² phase 3	2017	157	156	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	69.7 (8.7)^a	70.8 (8.7)^a	3.9	39 (24.8)	28 (17.9)	8 (5.1)	4 (2.6)
TERRAIN⁴³ phase 2	2016	184	191	Enzalutamide + ADT	Placebo + ADT	71 (50-96)	71 (48-91)	20.0^b	52 (28.4)	23 (12.2)	31 (16.9)	14 (7.4)
Sun et al⁴⁴ phase 3	2016	143	71	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	68.2 (8.3)^a	67.7 (7.8)^a	12.9	38 (26.6)	18 (25.4)	NR	NR
STRIVE M1⁴⁵ phase 3	2016	127	129	Enzalutamide + ADT	Bicalutamide + ADT	72 (46-92)	74 (50-91)	16.7	NR	NR	NR	NR
COU-AA-302⁴⁶ phase 3	2015	546	542	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	71 (44-95)	70 (44-90)	49.2	311 (57.4)	215 (39.8)	106 (19.6)	63 (11.7)
COU-AA-301⁴⁷ phase 3	2012	797	398	Abiraterone acetate + prednisolone + ADT	Placebo + prednisolone + ADT	69 (42-95)	69 (39-90)	20.2	235 (29.7)	91 (23.1)	72 (9.1)	23 (5.8)
AFFIRM⁴⁸ phase 3	2012	800	399	Enzalutamide + ADT	Placebo + ADT	69 (41-92)	69 (49-89)	14.4	119 (14.9)	54 (13.5)	NR	NR

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Abbreviations: ADT, androgen deprivation therapy; AG, groups A and G from the STAMPEDE trial; AJ, groups A and J from the STAMPEDE trial; CV, cardiovascular; CTCAE, Common Terminology Criteria for Adverse Events; ITT, intention to treat; NR, not reported; NSAA, nonsteroidal antiandrogen; M0 HSPC, nonmetastatic hormone-sensitive prostate cancer; M1 HSPC, metastatic hormone-sensitive prostate cancer; M1 CRPC, metastatic castration-resistant prostate cancer; M0 CRPC, nonmetastatic castration-resistant prostate cancer; RR, risk ratio; RT, radiotherapy.

^{^a}

Mean (SD) are reported.

^{^b}

Median follow-up in the control group was 16.7 months.

Studies investigated SOC used with ARSI monotherapy or combined with another ARSI or docetaxel. The following agents were combined with SOC therapy: abiraterone acetate and prednisolone (herein referred to as abiraterone acetate) (n = 9),^{1,2,29,33,35,42,44,46,47} abiraterone acetate and docetaxel (n = 1),³³ enzalutamide alone (n = 9),^{30,31,36,38,40,41,43,45,48,49} abiraterone acetate and enzalutamide (n = 2),^1,2 darolutamide alone (n = 1),³⁹ darolutamide and docetaxel (n = 1),³² and apalutamide alone (n = 2)^34,37 were studied. Of the 24 eligible studies, 18 reported CV events (75%): only 16 reported grade 3 or higher CV events (67%).

Quality Assessment

The overall risk of bias was low (eFigure 1 in Supplement 1). However, among 24 eligible studies, 6 (25%) did not report all grade CV events, and 8 (33%) did not report grade 3 or higher CV events. Nonetheless, only 3 studies were deemed at high risk of bias due to missing outcome data.^29,33,45 Funnel plots were grossly symmetric across all variables (eFigure 2 in Supplement 1). Based on linear regression, Egger statistic did not demonstrate significant funnel plot asymmetry for either all grade or grade 3 or higher CV events.

CV Event Risk With ARSI Therapy

All Grade CV Events

The incidence of all grade CV events was 22.0% (1717 of 7813) in patients receiving SOC and 36.6% (3479 of 9513) with addition of an ARSI (n = 18 RCTs, n = 17 326 patients; RR, 1.75; 95% CI, 1.50-2.04; P < .001) (Figure 2; eFigure 3 in Supplement 1). An increased risk of all grade CV events was associated with addition of an ARSI across all disease states: 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 < .001), M0 CRPC (RR, 1.79; 95% CI, 1.13-2.81; P = .01), and M1 CRPC (RR, 1.46; 95% CI, 1.16-1.83; P = .001). There was no significant difference in the pooled RR across disease states (χ² = 3.49; P = .32).

Figure 2. — AG indicates groups A and G from the STAMPEDE trial; AJ, groups A and J from the STAMPEDE trial; CRPC, castration-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer; M0, locally advanced; M1, metastatic; RR, risk ratio.

Increased risk of CV events was observed across all ARSI agents, although for apalutamide, there was only a single study available for comparison (eFigure 4 in Supplement 1). Subgroup differences were noted (χ² = 78.30, P < .001) with highest CV event rate observed with a combination of abiraterone acetate and enzalutamide (RR, 2.92; 95% CI, 2.59-3.30; P < .001), and lowest CV event rate with darolutamide (RR, 1.30; 95% CI, 1.09-1.54; P = .003).

Grade 3 or Higher CV Events

ARSI use was associated with increased risk of grade 3 or higher CV events, from 7.8% to 15.6% (16 RCTs: n = 15 813 patients; RR, 2.10; 95% CI, 1.72-2.55; P < .001) (Figure 3; eFigure 3 in Supplement 1). An association with increased grade 3 or higher CV events was observed across all disease subgroups: M0 HSPC (RR, 3.80; 95% CI, 2.48-5.84; P < .001), M1 HSPC (RR, 2.06; 95% CI, 1.47-2.87; P < .001), M0 CRPC (RR, 1.59; 95% CI, 1.23-2.06; P < .001), M1 CRPC (RR, 2.03; 95% CI, 1.53-2.68; P < .001). There was a significant difference in the pooled RR across disease states (χ² = 11.72; P = .008).

All ARSI agents were associated with an increased risk of grade 3 or higher CV events, although in patients taking darolutamide, there was only a single study available for comparison (eFigure 5 in Supplement 1). Subgroup differences were observed based on ARSI agent (χ² = 32.87; P < .001). The greatest risk of grade 3 or higher CV events was observed among patients treated with a combination of abiraterone acetate and enzalutamide (RR, 4.08; 95% CI, 3.01-5.52; P < .001), and lowest risk with apalutamide (RR, 1.39; 95% CI, 1.13-1.72; P < .001).

Secondary Outcomes

Secondary outcomes of grade 3 or higher events within CV subcategories were available for most included studies: hypertension (n = 22 studies, 92%), ACS (n = 19 studies, 79%), cardiac dysrhythmia (n = 17 studies, 71%), cerebrovascular (n = 17 studies, 71%), CV-related death (n = 17 studies, 71%), and venous thromboembolism (n = 17 studies, 71%). ARSI use was associated with increased risk of grade 3 or higher hypertension (RR, 2.25; 95% CI, 1.74-2.90; P < .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P < .001), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P < .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P < .001), and CV-related death (RR, 2.02; 95% CI, 1.32-3.10; P = .001). There was, however, no difference in the RR of grade 3 or higher venous thromboembolism with ARSI use (Figure 4; eFigure 3 in Supplement 1).

Figure 4. — CRPC indicates castration-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer; M0, locally advanced; M1, metastatic; RR, risk ratio.

Sensitivity Analysis

Substantial heterogeneity was observed in the RR of all grade (I² = 88%, P < .001) and grade 3 or higher (I² = 70%, P < .001) CV events. Previous studies on docetaxel use reported a possible increase in CV toxic effects.⁵⁰ Three trials^30,32,33 administered docetaxel as part of SOC, while 7 permitted the use of early or prior docetaxel.^{2,31,34,44,47,48} We found no statistically significant subgroup difference attributed to docetaxel exposure for all grade (χ² = 1.02, P = .31) and grade 3 or higher (χ² = 0.24, P = .62) CV events (eFigure 6 in Supplement 1).

Combination therapy with doublet ARSI was investigated in the STAMPEDE trial using a combination of abiraterone acetate and enzalutamide in both M0 HSPC and M1 HSPC settings.^1,2 We found a statistically significant subgroup difference attributed to combination ARSI use for both all grade (χ² = 42.78, P < .001) and grade 3 or higher (χ² = 20.29, P < .001) (eFigure 6 in Supplement 1) CV events.

Furthermore, metaregression analysis suggested that length of follow-up and combination ARSI use were significantly associated with a higher RR of CV events among ARSI-treated patients (eTable 4 in Supplement 1).

Quality of Evidence

The quality of evidence was summarized using the GRADE approach (eTable 5 in Supplement 1). We judged the certainty of evidence as moderate for all grade CV events and high for grade 3 or higher CV events based on high-quality RCTs, low risk of bias, sample size, and the magnitude of treatment effect.

Discussion

To our knowledge, this is the largest meta-analysis highlighting the increased risk of CV toxic effects associated with ARSI therapy across the PCa disease spectrum. The inclusion of contemporary HSPC trials made it possible, for the first time, to demonstrate a 2-fold increase in CV morbidity associated with the addition of an ARSI, and up to a 4-fold risk associated with the combined use of 2 ARSIs. We observed an increased risk of experiencing grade 3 or higher hypertension, ACS, cardiac dysrhythmia, and cerebrovascular events. Notably, a 2-fold increase in risk of a CV-related death was also observed with addition of an ARSI, though absolute risk of CV-related death was low. These findings are consistent with previous retrospective and observational studies^49,50 and should be discussed while counselling patients when commencing ARSI therapies.

Our results provide robust data compared with previous smaller meta-analyses based predominantly on CRPC trials.^{18,19,20,21,22} We observed a higher RR of CV events with ARSI therapy in comparison with previous studies, which may be due to longer trial follow-up, inclusion of additional HSPC studies, and variations in definitions of CV toxic effects used across studies. Uniquely, we report contemporary data from 12 HSPC trials, highlighting increased CV risk with earlier initiation of ARSI therapy compared with CRPC. One potential explanation for this finding may be a greater lifetime exposure to intensive androgen suppression with use of ARSI therapy in the HSPC setting, and the inclusion of recent studies using dual ARSI therapy.

Our study highlights the potential variation in CV events among different therapeutic antiandrogenic drug combinations. We found that treatment with enzalutamide and abiraterone acetate together was the most cardiotoxic, followed by use of either enzalutamide or abiraterone alone. In patients receiving dual ARSI treatment, we found that there was up to a 4-fold increase in grade 3 or higher CV events, which was also observed in the PLATO study.⁵¹ Both darolutamide and apalutamide were the least cardiotoxic agents based on currently available trial data. However, these results should be interpreted with caution as they may reflect patient selection and shorter trial follow-up, rather than a true difference in CV event risk with individual ARSI agents.

Physiological consequences of complete blockade of androgen production or androgenic action include insulin resistance, loss of muscle and bone mass, and an increase in fat distribution/composition, which are thought to accelerate the development of atherosclerosis and CV events.⁵² When applying these results to everyday clinical practice, it is important to understand that these drugs may affect patients with preexisting CV conditions more adversely than the clinical trial patient population, with health systems data illustrating up to 67% of patients receiving an ARSI have at least 1 CV comorbidity. Patients with 3 or more CV morbidities have been shown to experience a higher all-cause mortality than otherwise similar ARSI-treated patients without CV disease (RR 1.56; 95% CI, 1.29-1.88).⁵³ This highlights the importance of conducting outcome evaluation among patients not meeting strict trial eligibility criteria in the clinical setting. Notably, 17.8% of ADT-treated patients with preexisting CV disease in the HERO trial experienced a major adverse CV event within 1 year of treatment initiation,⁵⁴ and 71% of patients who experienced a fatal CV event in the PROSPER trial had a history of CV disease.³⁸ Risk scores, such as the Framingham Risk Score or QRISK2 score, have previously been used to estimate 10-year CV event risk in patients on ADT.^55,56 There is, however, a clear need for further data to stratify patients planned to commence ARSIs by preexisting comorbidities. By estimating baseline CV risk, clinicians can assess additional risks posed by ARSI therapy and consider appropriate management strategies depending on individual patient factors, including the potential future requirement for CV medications and their possible drug-drug interactions.^57,58,59 It is clear from our results that this ethos of risk management is even more important when considering combination ADT/ARSI use. Thus, due to the current lack of supporting evidence, comprehensive baseline CV risk assessment and implementation of evidence-based preventative strategies are crucial prior to initiating ARSI treatment in patients with preexisting CV risk factors. This highlights the importance of a multidisciplinary approach involving cancer physicians, primary care physicians and cardio-oncologists to ensure longitudinal CV care, especially for patients at increased CV risk.

Limitations

This study’s results should be interpreted in the context of the following limitations. First, we observed substantial heterogeneity despite inclusion of only RCT data and stratification by disease subtype. Potential explanations may include variations in collection of AE data, follow-up frequency, and follow-up duration between trials. We observed potential risk of bias due to method of AE reporting or missing outcome data among some studies. Where feasible, we attempted to account for such heterogeneity statistically and highlighted a greater frequency of CV events with longer trial follow-up. Second, CV outcomes were not consistently prespecified across all studies, including 2 studies where CTCAE v3.0 was used,^46,47 which may potentially bias measurement of these outcomes. However, we believe that these factors would be equally balanced between treatment and control groups and therefore unlikely to substantially affect our findings. Third, improved survival with ARSIs could manifest as a higher captured incidence of CV events. It is impossible to account for this given lack of time to event data and may be addressed in future studies using competing risks analysis as part of individual patient data meta-analyses. Additionally, we were also unable to account for established baseline CV risk factors from a majority of the trials and expect a higher frequency of preexisting CV morbidity resulting in an increased risk of CV events in the clinical setting.

Conclusions

This systemic review and meta-analysis provides up-to-date evidence of increased CV events in patients with PCa receiving ARSI with conventional ADT. As use of combination therapy becomes more widespread, particularly in earlier disease settings, there is greater need to evaluate and optimize baseline CV risk prior to commencing ARSI therapy.

Supplement 1.

eText. Search Strategy

eTable 1. CTCAE v4.0 Definitions for Classifying CV Adverse Events

eTable 2. Characteristics of Included Studies

eTable 3. Meta-Regression Analysis

eTable 4. GRADE Assessment for Certainty of Evidence

eFigure 1. RoB2 Tool Assessing Risk of Bias for CV Events

eFigure 2. Funnel Plots for the Examination of Small Study Effects for (A) All Grade CV Events and (B) Grade ≥ 3 CV Events

eFigure 3. Incidence Rates for (A) Primary Outcomes and (B) Secondary Outcomes

eFigure 4. Sub-Group Analysis of All Grade CV Events Based on ARSI

eFigure 5. Sub-Group Analysis of Grade ≥3 CV Events Based on ARSI

eFigure 6. Sensitivity Analysis of (A) All Grade CV Events and (B) Grade ≥3 CV Events

jamaoncol-e241549-s001.pdf^{(1.7MB, pdf)}

Supplement 2.

Data Sharing Statement

jamaoncol-e241549-s002.pdf^{(16.5KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eText. Search Strategy

eTable 1. CTCAE v4.0 Definitions for Classifying CV Adverse Events

eTable 2. Characteristics of Included Studies

eTable 3. Meta-Regression Analysis

eTable 4. GRADE Assessment for Certainty of Evidence

eFigure 1. RoB2 Tool Assessing Risk of Bias for CV Events

eFigure 2. Funnel Plots for the Examination of Small Study Effects for (A) All Grade CV Events and (B) Grade ≥ 3 CV Events

eFigure 3. Incidence Rates for (A) Primary Outcomes and (B) Secondary Outcomes

eFigure 4. Sub-Group Analysis of All Grade CV Events Based on ARSI

eFigure 5. Sub-Group Analysis of Grade ≥3 CV Events Based on ARSI

eFigure 6. Sensitivity Analysis of (A) All Grade CV Events and (B) Grade ≥3 CV Events

jamaoncol-e241549-s001.pdf^{(1.7MB, pdf)}

Supplement 2.

Data Sharing Statement

jamaoncol-e241549-s002.pdf^{(16.5KB, pdf)}

[coi240017r1] 1.Attard G, Murphy L, Clarke NW, et al. ; Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators . Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022;399(10323):447-460. doi: 10.1016/S0140-6736(21)02437-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240017r2] 2.Attard G, Murphy L, Clarke NW, et al. ; STAMPEDE investigators . Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023;24(5):443-456. doi: 10.1016/S1470-2045(23)00148-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240017r3] 3.Parker CC, James ND, Brawley CD, et al. ; STAMPEDE Trial Collaborative Group . Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial. PLoS Med. 2022;19(6):e1003998. doi: 10.1371/journal.pmed.1003998 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240017r4] 4.IMS Institute for Healthcare Informatics . Global oncology trend report: a review of 2015 and outlook to 2020. Published June 2016. Accessed May 7, 2024. https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/global-oncology-trend-report-2016.pdf

[coi240017r5] 5.Veccia A, Maines F, Kinspergher S, Galligioni E, Caffo O. Cardiovascular toxicities of systemic treatments of prostate cancer. Nat Rev Urol. 2017;14(4):230-243. doi: 10.1038/nrurol.2016.273 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

Omar El-Taji, MBChB, MRes

Samih Taktak, MBBS

Craig Jones, MBChB, MRes

Mick Brown, PhD

Noel Clarke, MBBS, ChM

Ashwin Sachdeva, MBBS, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Protocol and Registration

Search Strategy

Inclusion and Exclusion Criteria

Outcome Measures

Data Extraction and Quality Assessment

Statistical Analysis

Subgroup and Sensitivity Analysis

Results

Studies Evaluated

Figure 1. PRISMA Flow Diagram.

Table. Characteristics of Included Studies.

Quality Assessment

CV Event Risk With ARSI Therapy

All Grade CV Events

Figure 2. Meta-Analysis of Relative Risk for All Grade Cardiovascular Events Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy.

Grade 3 or Higher CV Events

Figure 3. Meta-Analysis of Relative Risk for Grade 3 or Higher Cardiovascular Events Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy.

Secondary Outcomes

Figure 4. Meta-Analysis of Relative Risk for Secondary Outcomes Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy.

Sensitivity Analysis

Quality of Evidence

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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