Clinical-Prostate cancer
The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study

https://doi.org/10.1016/j.urolonc.2018.11.017Get rights and content

Highlights

  • Objective: assess statin use on outcomes in men with advanced prostate cancer.

  • Patients in this study had advanced cancer on androgen deprivation therapy.

  • Statin use associated with improved oncologic outcomes in Veterans.

Abstract

Background

Statins are thought to possess antineoplastic properties related to their effect on cell proliferation and steroidogenesis. Progression to castrate resistant prostate cancer (CaP) includes de-regulation of androgen synthesis suggesting a role for statins in this setting. Our goal was to assess the role of statin use on oncologic outcomes in patients with advanced CaP being treated with androgen deprivation therapy (ADT).

Methods

The national VA database was used to identify all men diagnosed with CaP who were treated with ADT for at least 6 months between 2000 and 2008 with follow-up through May 2016. Our cohort was stratified based on statin use of at least 6 months duration during the same time. Multivariable Cox proportional hazards analyses with inverse propensity score weighted (IPSW) adjustment were calculated to assess for primary outcomes of CaP-specific survival (CSS), overall survival (OS) and skeletal related events (SREs).

Results

A total of 87,346 patients on ADT were included in the study cohort, 53,360 patients used statins and 33,986 did not. Statin users were younger in age (median 73 vs. 76, P < 0.001), more likely to have a higher Charlson comorbidity index (CCI) >3 (3.1% vs. 2.5%, P < 0.001) and more likely to have a high grade (Gleason score 8–10) cancer (12.3% vs. 10.9%, P < 0.001). Statin users had longer OS (median 6.5 vs. 4.0 years P < 0.001) and decreased death from CaP (5-year CSS 94.0% vs. 87.3%, P < 0.001). Statin use was also associated with longer time to a SRE (median 5.9 vs. 3.7 years, P < 0.001). On multivariable Cox proportional hazards analysis with inverse propensity score weighted, statin use was an independent predictor of improved OS (hazard ratio [HR] 0.66, confidence interval [CI] 0.63–0.68; P < 0.001), CSS (HR 0.56, 95% CI 0.53–0.60; P < 0.001), and SREs (HR 0.64, 95%CI 0.59–0.71; P < 0.001) when controlling for age, race, Charlson comorbidity index, prostate-specific antigen, and Gleason score.

Conclusion

The use of statins in men on ADT for CaP is associated with improved CSS and OS. Statins are inexpensive, well-tolerated medications that offer a promising adjunct to ADT, but require further prospective studies.

Introduction

Statins are one of the most commonly prescribed medications for hypercholesterolemia worldwide, with 1 in 4 Americans over 45 taking a daily statin [1]. Statins lower cholesterol levels by inhibiting the 3-hydroxy-3-methylglutaryl-coenzyme A enzyme at the rate limiting step in the mevalonate pathway of cholesterol synthesis [2]. Recent research has focused on the antineoplastic role of statins through their impact on cell proliferation, inflammation, membrane organization, and steroidogenesis [3]. The androgen-dependent nature of prostate cancer (CaP) has made it a perfect candidate for study of statin based cancer prevention and therapy. Additionally, recent Phase III trials have defined a role for androgen deprivation therapy (ADT) in combination with docetaxel or abiraterone for metastatic hormone-sensitive CaP suggesting combination therapy improves the ability of ADT to lengthen survival [4], [5].

Observational studies suggest that long-term statin therapy may prevent aggressive CaP [3]. The role of statins in decreasing CaP specific and overall cancer mortality is more heavily disputed [6]. Specifically, there are few studies focusing on the role of statins in advanced CaP and prevention of progression to castrate resistant CaP and subsequent death. It is now recognized that castration resistance is at least partially related to CaP cells’ ability to undergo intratumoral steroidogenesis sufficient to activate the androgen receptor [3], [7]. This may explain the resistance to ADT seen in many patients with advanced CaP. Statins may work synergistically with ADT by lowering cholesterol and hence, decreasing the availability of the major substrate for androgen synthesis [3]. Furthermore, statins have also been shown to down-regulate androgen receptors via proteolysis, alter cell signaling pathways, and induce apoptosis of proliferating cells [3], [8]. Our goal was to assess the effect of statin use on oncologic outcomes in patients with advanced CaP at the time of ADT initiation.

Section snippets

Data source

The study was approved by the local Institutional Review Board. The Veterans Health Administration (VA) health system is one of the largest integrated health systems in the United States. All care provided to veterans is recorded in their electronic health record—the Veterans Information System Technology Architecture. All information regarding patient care is extracted from Veterans Information System Technology Architecture systems and stored on the Corporate Data Warehouse (CDW). The

Results

A total of 87,346 patients on ADT were included in the study cohort, of which 53,360 patients used statins and 33,986 did not. The statin cohort was younger in age (median 73, interquartile range [IQR] 67–78) at ADT initiation than the nonstatin cohort (median 76, IQR 70–81), P < 0.001. Both nonstatin and statin cohorts were composed of primarily Caucasians (60.5 and 65.2%, P < 0.001). Individuals taking statins were more likely to have a CCI > 3 (3.1%) compared to nonstatin users (2.5%), P <

Discussion

Advanced CaP has classically been treated with ADT with a median survival of less than 2 years once castration resistance develops [16]. Recent research has led to the understanding that despite “castration resistance,” progression of CaP may continue to be driven by androgen signaling suggesting the existence of a de novo intracellular androgen synthesis pathway [2], [3]. This has led to the discovery of new therapeutic agents such as enzalutamide and abiraterone which target the androgen

Conclusion

Statins are widely available, low-risk medications with increasing evidence of antineoplastic properties in the setting of CaP. Our study adds to the existing literature on the role of statins in progression of advanced CaP and is the largest study to date to look at statin use in the setting of ADT. Through demonstrating improved OS, decreased death from CaP, and increased time to SRE, our research suggests that statin use in conjunction with ADT offer a promising adjunct to ADT in the

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the William S. Memorial Veterans Hospital. The contents do not represent the views of the U. S. Department of Veterans Affairs or the United States Government. The authors would like to acknowledge and thank all the women and men that have served their country in the Unites States Armed Forces.

References (28)

  • LE Price et al.

    The Veterans Affairs's Corporate Data Warehouse: uses and implications for nursing research and practice

    Nurs Adm Q

    (2015)
  • Webmaster PBM: Pharmacy Benefits Management Services Home. Available at: https://www.pbm.va.gov/, accessed February 27,...
  • RE Coleman

    Clinical features of metastatic bone disease and risk of skeletal morbidity

    Clin Cancer Res

    (2006)
  • A Aly et al.

    Measurement of skeletal related events in SEER-medicare: a comparison of claims-based methods

    BMC Med Res Methodol

    (2015)
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    Disclosures: The authors have nothing to disclose.

    Funding: This work was supported by a Department of Defense grant via the Prostate Cancer Research Program #PC150221.

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