Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER

Joshua, Anthony M.; Armstrong, Andrew J.; Crumbaker, Megan; Scher, Howard I.; Bono, Johann S. de; Tombal, Bertrand; Hussain, Maha; Sternberg, Cora N.; Gillessen, Silke; Carles, Joan; Fizazi, Karim; Lin, Po-Han; Duggan, William; Sugg, Jennifer; Russell, David; Beer, Tomasz M.

doi:10.1016/j.ejca.2022.04.005

Cited by 17 publications

(9 citation statements)

References 37 publications

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“…In the subgroup analysis of ACM, we included two studies that used abiraterone or enzalutamide as the primary treatment. The result revealed statin use may reduce the risk of ACM when accepting abiraterone or enzalutamide, which was consistent with previous meta-analyses [ 44 ]. As the selection of primary treatment depends on certain subtypes of PCa, the patients involved in these two studies were all diagnosed with metastatic castration-resistant prostate cancer (mCRPC).…”

Section: Discussionsupporting

confidence: 91%

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies

Sun

et al. 2022

Journal of Oncology

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Objective. Although the prognostic effect of statins on patients with prostate cancer (PCa) has been frequently evaluated, a consistent result is still lacking. We aimed to evaluate the association between statin use and mortality among patients with PCa after definite therapies. Methods. A systematic search of PubMed and other databases for cohort studies about the effect of statins on patients with PCa was performed until April 2022. Meta-analysis was performed using R software version 4.1.2. Results. 24 cohort studies involving 369, 206 participants were finally included. We found statin use significantly reduced the risk of prostate cancer-specific mortality (PCSM) with a pooled hazard ratio (pHR) = 0.76 (95% CI: 0.69–0.84, 18 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.77–0.85) and patients who accepted androgen deprivation therapy (ADT): pHR = 0.69 (95% CI: 0.59–0.81). Statin use was also associated with a 24% reduction in the risk of all-cause mortality (ACM): pHR = 0.76 (95% CI: 0.68–0.85, 17 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.78–0.85) and patients treated with ADT: pHR = 0.72 (95% CI: 0.63–0.82) or radiotherapy (RT): pHR = 0.68 (95% CI: 0.50–0.93). Conclusion. In conclusion, the use of statins could promote the prognosis of patients with PCa, especially for postdiagnostic users. For patients who received either ADT or radical prostatectomy (RP), statin use could decrease the PCSM. As for those who received either ADT or RT, statin use could decrease the ACM.

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Section: Discussionsupporting

confidence: 91%

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies

Sun

et al. 2022

Journal of Oncology

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“… 108 A study of pooled data from three large randomized controlled trials (RCTs) of enzalutamide in CRPC found that statin use was associated with improved OS (HR 0.75, 95% CI 0.66–0.85). 109 A retrospective study of men treated with either abiraterone or enzalutamide in the post-docetaxel setting also found statin use was associated with improved OS (HR 0.57, 95% CI 0.46–0.71). 110 …”

Section: Therapeutic Targeting Of Aberrant Lipid Metabolismmentioning

confidence: 97%

“…Metformin use in CRPC has been evaluated in retrospective cohorts, with improved outcomes in men treated with abiraterone, 107 but not docetaxel 145 or enzalutamide. 109 There have been two prospective clinical trials of metformin in men with CRPC, showing conflicting results. The SAKK 08/09 trial, a phase II study of metformin in CRPC, found that of the 44 enrolled patients, 36% were progression free at 12 weeks, and 9% progression-free at 24 weeks.…”

Section: Therapeutic Targeting Of Aberrant Lipid Metabolismmentioning

confidence: 99%

Targeting lipid metabolism in metastatic prostate cancer

et al. 2023

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Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.

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“…Preclinical studies have shown that metformin exerts antitumor effects against various cancers, including pancreatic, colon, breast, and prostate cancers [16][17][18][19][20]. Metformin also enhances the in vitro activity of various chemotherapeutic agents, such as doxorubicin in MCF-7 and MDA-MB-231 breast cancer cells, gemcitabine in KLM-1R pancreatic cells, and cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells [21][22][23].…”

Section: Metformin In Clinical Trialsmentioning

confidence: 99%

Why Metformin Should Not Be Used as an Oxidative Phosphorylation Inhibitor in Cancer Patients

Sakellakis¹

2023

Chemotherapy

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Background: Preclinical studies have suggested that metformin exerts antitumor effects on various types of cancers. However, the results of human clinical trials have been inconsistent. Summary: Metformin is widely considered to be a prime example of a clinically relevant compound that inhibits oxidative phosphorylation (OXPHOS). However, the efficacy of metformin in inhibiting OXPHOS in cancer patients remains uncertain. The available evidence suggests that the plasma concentration of metformin remains within the micromolar range when administered at therapeutic doses. While millimolar concentrations are necessary to inhibit complex I activity in isolated mitochondria, there is no evidence supporting the idea that metformin accumulates within the mitochondria. Metformin exerts a modest effect on the adenosine diphosphate to adenosine triphosphate (ATP) ratio, resulting in AMP-activated protein kinase activation, which promotes ATP-generating catabolic pathways and restores cellular energy balance. Key Messages: The value of metformin as an OXPHOS inhibitor for cancer treatment is debatable, and caution should be exercised while using metformin for this purpose.

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Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER

Cited by 17 publications

References 37 publications

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies

Targeting lipid metabolism in metastatic prostate cancer

Why Metformin Should Not Be Used as an Oxidative Phosphorylation Inhibitor in Cancer Patients

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