Analysis underscores cardiotoxicity risks with androgen signaling inhibitors in CRPC

A new analysis corroborates prior research showing that androgen signaling inhibitors (ASIs) increase cardiotoxicity risk in men with castration-resistant prostate cancer (CRPC)^.1

The retrospective analysis, which was published in Prostate Cancer and Prostatic Diseases, showed that the ASIs abiraterone acetate (Zytiga) and enzalutamide (Xtandi) both increased cardiotoxicity risk, but that their specific impact varied. The overall risk of cardiac disorders was higher with abiraterone versus enzalutamide; whereas enzalutamide was associated with a higher risk of hypertension.

“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,” the investigators wrote.

Overall, the study assessed data from 7103 patients enrolled across 7 randomized controlled trials. The trials ranged from phase 2 to phase 4, and included patients with either metastatic or nonmetastatic CRPC who were treated with abiraterone or enzalutamide. The investigators used the Common Terminology Criteria for Adverse Events to define the study’s 4 outcome measures: cardiac disorder of any grade, high-grade cardiac disorder, hypertension across all grades, and high-grade hypertension.

Pairwise meta-analysis showed abiraterone was associated with a higher risk of any grade cardiac disorder (risk ratio [RR], 1.34; 95% CI, 1.05-1.73), as well as severe grade cardiac disorders (RR, 1.71; 95% CI, 1.16-2.53). The risk of any grade (RR, 2.66; 95% CI, 1.93-3.66) and severe grade (RR, 2.79; 95% CI, 1.86-4.18) hypertension was higher with enzalutamide.

A head-to-head comparison using surface under cumulative ranking curves (SUCRAs) showed that abiraterone had a higher probability for any grade and severe grade cardiac disorders versus enzalutamide at 84.84% versus 62.83% and 85.12% and 50.76%, respectively. SUCRAs showed that the probability of hypertension of any grade (99.43% vs 49.08%) and severe grade (89.71% vs 49.37%) was higher with enzalutamide versus abiraterone, respectively.

Outcomes align with prior research

The outcomes from this retrospective analysis were similar to those from a retrospective analysis presented earlier this year at the 2020 Genitourinary Cancers Symposium.² That analysis used adverse event (AE) data from VigiBase, which is the World Health Organization’s database of individual case safety reports. The investigators reviewed that data for cardiotoxicities related to enzalutamide or abiraterone treatment in patients with prostate cancer. The study defined the cardiac AEs using terminology from the Medical Dictionary for Regulatory Activities.

Overall, the VigiBase review yielded 8203 AEs for abiraterone and 26,024 AEs for enzalutamide. Cardiotoxicities made up 9.9% (n = 808) of the AEs in the abiraterone group compared with 3.8% (n = 1000) in the enzalutamide group. The overall odds of experiencing a cardiac AE were higher for a patient taking abiraterone (ROR, 1.59; 95% CI, 1.48-1.71), as were the odds of arrythmia (ROR, 2.04; 95% CI, 1.82-2.29), heart failure (ROR, 3.02; 95% CI, 2.60-3.51), and myocardial infarction (1.35; 95% CI, 1.16-1.58).Enzalutamide, on the other hand, was not associated with a disproportionality signal for cardiac events, either overall or with any specific cardiac AE subtype.

“We found significantly increased odds of cardiac events for abiraterone but not for enzalutamide. Clinicians may need to consider these findings in the context of their patients’ comorbidities when prescribing ADT,” the authors concluded.

References

1. Lee HY, Chen H-L, Teoh J Y-C, et al. Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses [published online August 28, 2020]. Prostate Cancer Prostatic Dis. doi: 10.1038/s41391-020-00275-3

2. Cone EB, Reese S, Marches M, et al. Association of abiraterone and higher odds of cardiac complications compared to enzalutamide. J Clin Oncol 38, 2020 (suppl 6; abstr 70).