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Re: The Incidence and Relative Risk of Cardiovascular Toxicity in Patients Treated with New Hormonal Agents for Castration-resistant Prostate Cancer

European Urology, Volume 69, Issue 1, January 2016, Pages 177-178

Experts’ summary:
Iacovelli et al provide the first observational support that the use of cytochrome P450 family 17 (CYP-17) inhibitors or enzalutamide is associated with an increase in the risk of cardiovascular (CVS) toxicity. The authors performed a meta-analysis of randomized controlled trials involving 6735 castration-resistant prostate cancer (CRPC) patients who were treated with either abiraterone (2 studies, n = 1333), orteronel (2 studies, n = 1516), enzalutamide (2 studies, n = 1672), or a control (all 6 studies, n = 3311). CVS toxicity was defined as the onset of ischemic heart disease, myocardial infarction, arrhythmia, or heart failure. Overall, the use of these hormonal agents was associated with a 32% higher risk of CVS toxicity compared to controls, but not grade 3–4 toxicity. Although these differences were statistically significant, differences in absolute risk were small (14.8% vs 11.5%). While CYP-17 inhibitors were associated with statistically significant risks for all (relative risk [RR] 1.47) and high-grade cardiac toxicity (RR 1.55) compared to controls, the usage of enzalutamide was not associated with CVS toxicity. The association of these hormonal agents (and in particular enzalutamide) with the development of hypertension was significant compared to controls. Interestingly, enzalutamide, but not CYP-17 inhibitors, was associated with a statistically significant risk of developing high-grade hypertension (RR 2.67). The incidence of CVS toxicity and hypertension was significantly higher if these agents were used before compared to after docetaxel.
Experts’ comments:
In the current era, more robust androgen deprivation can be achieved with the use of CYP-17 inhibitors or more efficient androgen receptor blockade. The question of whether this so-called supercastration also translates to higher rates of CVS toxicity is interesting and important given the fact that contemporary survival of patients with CRPC is >2.5 yr [1]. To the best of our knowledge, this study is the first to investigate this issue. The study suggests that this is indeed the case, albeit with a very modest absolute risk reduction and no significant effect on high-grade CVS toxicity. This probably stems from the fact that the analysis was performed in patients (and controls) who were already on long-term androgen deprivation therapy. In addition, recent data indicate that in patients who have CVS risk factors, most CVS events develop relatively early, and therefore such events have already occurred in those patients who are predisposed to CVS disease [2]. Furthermore, patients with a significant history of CVS disease were excluded from the studies analyzed. Nevertheless, there is a clear signal that even in patients with castrate levels of testosterone, further testosterone elimination can potentiate CVS derangements. Are these effects solely caused by better testosterone suppression, which further eliminates the atheroprotective effects related to testosterone, or less feedback inhibition on the hypophysis that leads to higher, potentially atherogenic follicle-stimulating hormone levels, or off-target side effects of these drugs [3] and [4]? These hypotheses can be best tested in animal models.

The oncologic benefits of these agents in the setting of CRPC are clear and the modest effects on CVS events reported should not prevent their usage. Awareness, CVS monitoring, and potential pharmacologic and lifestyle modifications to prevent CVS toxicity are recommended. Special considerations and caution are warranted in trials examining the role of these agents earlier in the disease course [5].

Conflicts of interest

The authors have nothing to disclose.

References

  • [1] C. Ryan, et al. Lancet Oncol. 2015;16:152-160
  • [2] S. O’Farrell, et al. J Clin Oncol. 2015;33:1243-1251
  • [3] J. Bourghardt, et al. Endocrinology. 2010;151:5428-5437
  • [4] S. Hopmans, et al. Urol Oncol. 2014;32:1126-1134
  • [5] University of Sydney. Enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer (ENZAMET). https://clinicaltrials.gov/ct2/show/NCT02446405

Footnotes

Department of Surgery, Division of Urology, McMaster University, Hamilton, Ontario, Canada

Corresponding author. Department of Surgery, Division of Urology, McMaster University, 699 Concession Street, Hamilton, Ontario L8 V 5C2, Canada.


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