Urologic Oncology: Seminars and Original Investigations
Clinical-Prostate cancerThe impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study
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.
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Cited by (27)
Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER
2022, European Journal of CancerCitation Excerpt :There are mixed results for outcomes associated with statin use in patients with prostate cancer in epidemiologic and clinical studies [11,12]. For example, an observational study of 87,000 patients with prostate cancer showed that use of statins was associated with improved cancer-specific survival and overall survival (OS) in patients with advanced prostate cancer receiving ADT monotherapy [13]. Statin use by patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel or mitoxantrone in the phase III TROPIC trial was associated with a longer OS, although no significant differences in progression-free survival or response rates were observed [14].
Beta-Adrenergic Antagonists and Cancer Specific Survival in Patients With Advanced Prostate Cancer: A Veterans Administration Cohort Study
2021, UrologyCitation Excerpt :It is critical that research efforts focus on options that provide low cost, minimal side-effects, and significant improvement in survival. Our study suggests no PCa specific survival benefit associated with beta blockers or metoprolol specifically, which is notable given positive results with other agents such as statins and metformin in this population.21,27 This data challenges prior studies on beta-blockers and advanced PCa and will help appropriately focus future research in this arena.
The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy
2021, European UrologyCitation Excerpt :As statins improve cardiovascular health, they may combat some of the metabolic changes induced by androgen deprivation therapy (ADT) [11]. In a handful of observational studies that have examined statin use in combination with ADT, favourable outcomes have been observed [12–14]. Thus, we sought to examine the association between statin use and outcomes among men initiating ADT nested in a randomised controlled trial (RCT).
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.