Progress in Understanding What Is Being Statin(ed) in Prostate Cancer

In this issue of JAMA Oncology, Harshman et al¹ report longer time to progression (TTP) while receiving androgen deprivation therapy (ADT) for patients with prostate cancer who are using statins compared with nonusers (median TTP, 27.5 vs 17.4 months, respectively). The authors¹ propose a mechanism through statin-induced competitive inhibition of the androgen precursor, dehydroepiandrosterone-sulfate (DHEAS), uptake via an organic anionic transporting polypeptide (OATP) encoded by SLCO2B1. Preclinical mechanistic data support DHEAS uptake dependence on SLCO2B1 expression, and DHEAS uptake and cell proliferation are decreased at physiologic statin concentrations. As the authors¹ point out, the main challenges to the clinical findings of this study are potential inherent confounders and bias associated with any retrospective analysis, of which all cannot be accounted for in a multivariate analysis. For example, patients prescribed statin therapy had generally better prognostic features and likely represent a group more apt to seek early medical care and health maintenance, such as prostate-specific antigen (PSA) screening. Nevertheless, we are provided with intriguing evidence for a mechanism of how statins may exert an antitumor effect in patients being treated for prostate cancer.

The strongest clinical evidence for a cancer “protective effect” from statins, across a wide range of malignant neoplasms, was generated from a Danish, population-based observational study. Overall, patients prescribed statins prior to cancer diagnosis had a 15% risk reduction in all-cause and cancer-specific mortality.² The decrease in cancer-specific mortality was seen in 13 of 27 primary tumor sites, including the 4 most commonly diagnosed malignant neoplasms: lung, colon, breast, and prostate cancer. The authors² hypothesized that statins may act through several possible mechanisms: (1) disruption of cellular processes, such as cell signaling, cell-cycle progression, protein synthesis, and membrane integrity; (2) induction of apoptosis; (3) reduced angiogenesis; and/or (4) reduced serum cholesterol levels. Other studies have shown comparable findings, most evaluating statins in cancer prevention.^3,4 One of the most notable studies⁵ revealed a 50% relative risk reduction of colorectal cancer in patients prescribed statin therapy for at least 5 years. Despite these encouraging results, multiple negative observational studies and meta-analyses, coupled with a lack of strong mechanistic data, temper overall enthusiasm.⁶

More convincing clinical data for the ability of statins to improve advanced disease outcomes, rather than prevention, may exist for prostate cancer. Although there have been mixed results in multiple observational studies of statin use on prostate cancer mortality, a meta-analysis⁷ showed a 20% reduced risk of developing advanced prostate cancer. More recently, Yu et al⁸ demonstrated a decreased prostate cancer–specific mortality rate in those patients treated with a statin, with the greatest mortality benefit in patients on a statin prior to the diagnosis of prostate cancer.

Statins may have activity in prostate cancer through direct or indirect inhibition of the androgen axis. In advanced prostate cancer, patients are typically treated with ADT, suppressing the availability of testosterone ligand for androgen receptor (AR) signaling. Interestingly, as castration-resistant prostate cancer (CRPC) develops, intratumoral androgen levels remain elevated, prompting considerations of intratumoral androgen synthesis.^9-11 DHEAS, an adrenal androgen precursor, has been shown to play an important role in the development of CPRC with promotion of tumor growth through intracrine conversion to androgens that activate AR.¹²SLCO2B1 may be pivotal to the role of DHEAS in CRPC, as expression levels of SLCO2B1 have been shown to be significantly higher in CRPC compared with untreated primary prostate cancer samples.¹³ Furthermore, in patients with predominately localized disease, harboring the variant A allele in the SCLO2B1 single-nucleotide polymorphism (SNP) rs12422149 was associated with increased prostate cancer-specific mortality.¹³ Finally, from a cohort of patients with more advanced prostate cancer, Yang et al¹⁴ identified 3 SNPs in SLCO2B1 that were associated with shorter TTP while receiving ADT. Interestingly, patients with 2 copies of the variant G allele of SNP rs12422149 had a shorter TTP, and this SNP was associated with increased DHEAS import in prostate cancer cell lines.¹⁴

Although the evidence supporting the role of SLCO2B1 is emerging, other mechanisms may contribute to the antitumor properties of statins in prostate cancer. Statins primarily act through inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, preventing the formation of mevalonate and thereby inhibiting cholesterol synthesis, a potential substrate for intratumoral steroidogenesis. This is evidenced by a study¹⁵ which demonstrated that circulating serum cholesterol levels led to de novo intratumoral androgen synthesis and increased tumor size in a xenograft model. Moreover, inhibition of intratumoral steroidogenesis has been shown to be important clinically in the castration-resistant setting. Abiraterone acetate, a CYP17A1 inhibitor, blocks the conversion of pregnenolone to DHEAS and has been shown to improve overall survival in the prechemotherapy and postchemotherapy CRPC settings.

Harshman et al¹ have made a compelling argument for a biologic mechanism of action of statins in advanced prostate cancer through competitive inhibition of the uptake of DHEAS via SLCO2B1-encoded transporters. However, randomized, prospective validation of the clinical benefits of statin use in advanced prostate cancer is necessary. Currently, there are several clinical trials in the neoadjuvant setting that may offer pharmacodynamic information (NCT01821404, NCT01992042, NCT00572468). Another trial is evaluating the impact of atorvastatin on the rate of biochemical recurrence in patients with a Gleason score of 8 or greater, positive surgical margin, or pT3-T4 disease who underwent radical prostatectomy (NCT01759836).

However, based on current clinical and biologic evidence, statins may be most effective in patients with more advanced disease, in which DHEAS and intratumoral androgen synthesis have been shown to play a role in castration resistance. Therefore, a potential clinical setting for further investigation of statins is in patients with nonmetastatic CRPC, for whom there is no current standard of care, and in whom PSA could be evaluated in early trials as a clinical marker of response.

In all, Harshman et al¹ have conducted an interesting analysis linking in vitro preclinical data with retrospective patient outcomes, providing a framework for future evaluation. Nonetheless, the current data are not sufficient to support incorporation of statin use into clinical oncology practice for patients with prostate cancer, and additional studies are required.

Corresponding Author: Evan Y. Yu, MD, Seattle Cancer Care Alliance, 825 Eastlake Ave E, G4-800, PO Box 358081, Seattle, WA 98109-1024 (evanyu@u.washington.edu).

Published Online: May 7, 2015. doi:10.1001/jamaoncol.2015.0833.

Conflict of Interest Disclosures: None reported.