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Statin use before ADT delays prostate cancer progression
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Men with prostate cancer who used statins at the initiation of androgen deprivation therapy demonstrated a delayed time to progression, according to study findings.
Genetic variants of SLCO2B1 — a gene that transports drugs, including statins, and hormones into cells — have previously been associated with time to progression during ADT, according to study background.
Philip W. Kantoff, MD, chief of the division of solid tumor oncology, director of the Lank Center for Genitourinary Oncology and chair of the executive committee for clinical research at the Dana-Farber Cancer Institute, and colleagues hypothesized that statins may interfere with the uptake of dehydroepiandrosterone sulfate (DHEAS) — a precursor of testosterone and a substrate for SLCO2B1 — by tumor cells, thus, delaying resistance to ADT.
Philip W. Kantoff
Researchers sought to determine whether there was an interaction between statins and DHEAS influx in the prostate cancer cell lines transported through SLCO2B1. They also evaluated the association between time to disease progression and statin use among a cohort of patients with prostate cancer who were receiving ADT.
In vitro analyses indicated statins block DHEAS by competitively binding to SLCO2B1.
Based on these findings, the researchers conducted additional analyses in a cohort of 926 patients with hormone-sensitive prostate cancer who had been treated with ADT between 1996 and 2013. Thirty-one percent of the patients were taking a statin at the time of ADT initiation.
After a median follow-up of 5.8 years, 70% had disease progression. The overall median time to progression was 20.3 months (95% CI, 18-24). However, men who were taking statins had a longer median time to progression during ADT (27.5 months; 95% CI, 21.1-37.7) compared with nonusers (17.4 months; 95% CI, 14.9-21.1).
The association persisted in analyses adjusted for prognostic factors such as biopsy Gleason score, type of primary therapy and metastatic status (adjusted HR = 0.83; 95% CI, 0.69-0.99).
Statins also were associated with delayed progression in patients with metastases (adjusted HR = 0.79; 95% CI, 0.58-1.07) and without metastases (adjusted HR = 0.84; 95% CI, 0.67-1.06).
“We present a plausible mechanism by which statins may work in prostate cancer by decreasing the tumor’s available androgen pool and thus improving patient outcomes,” Kantoff said in a press release. “Further study is required to validate our findings.”
These results do not yet support the routine use of statins for prostate cancer, Jorge D. Ramos, DO, a medical oncologist with the Seattle Cancer Alliance and the University of Washington Medicine Harborview Medical Center, and Evan Y. Yu, MD, an associate professor in the department of medicine and the division of oncology at the University of Washington and a medical oncologist with the Seattle Cancer Alliance, wrote in an accompanying editorial.
“[The researchers] 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,” Ramos and Yu wrote. “However, randomized, prospective validation of the clinical benefits of statin use in advanced prostate cancer is necessary.
“[The researchers] 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,” they wrote. – by Anthony SanFilippo
Disclosure: One researcher reported employment with Apple Tree Pharmaceuticals and stock ownership in Tokai Pharmaceuticals. The other researchers, Ramos and Yu reported no relevant financial disclosures.
Perspective
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Igor Astsaturov, MD, PhD
This paper is an important finding because it introduces a new and previously unknown mechanism for possible management of metastatic prostate cancer.
We know that prostate cancer cells are dependent on androgens — the male steroid hormone — for growth. The uptake of androgen precursors, such as dehydroepiandrosterone sulfate, is dependent on a membrane protein called SLCO2B1. What this paper shows is that statins block SLCO2B1 and suppress the uptake of androgens and growth of prostate cancer cells. As a result, patients using statins had a longer benefit of hormonal deprivation therapy than non-users.
This represents another unique chapter in the ongoing story of drug repurposing where we take drugs that are on the market and find other uses for them. Statins have a known effect on lowering cholesterol, and we now see that they have an effect on cancer cell function.
Whether this finding translates into demonstrated clinical benefit will require a prospective randomized study. We would want to determine if the effect was lost in hormone-independent prostate cancers. Would the introduction of statins reverse resistance and/or sensitize hormone-refractory prostate cancer to androgen deprivation?
These are questions for the future that will determine if this is a clinically useful strategy. For now, I would congratulate my colleagues at Dana-Farber on a very well done study.
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