Concurrent Statin Use in ADT Patients Reduced All Cause, Prostate Cancer-Specific Deaths

Philip Kantoff, MD

Patients who were taking statins while also undergoing androgen deprivation therapy (ADT) may experience a reduction in all-cause and prostate cancer-specific deaths, according to new research from the Dana-Farber Cancer Institute. A retrospective study involving statin use was conducted in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. Findings were published in JAMA Oncology.

Analyzing prostate cancer cell lines, the researchers also demonstrated that statins and dehydroepiandrosterone sulfate (DHEAS), a precursor of testosterone, compete for the SLCO2B1 cellular transporter, which facilitates entry into prostate cells, thus providing a potential mechanism of action.

The analysis revealed that 31% of patients were taking a statin—atorvastatin, fluvastatin, pravastatin, or simvastatin&mdash;at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median time to progression (TTP) during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001).

In addition, researchers saw a 17% reduction in the hazard of progression during ADT after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83; 95% CI, 0.69-0.99; P = .04) such as Gleason score at biopsy, type of primary therapy be it radical prostatectomy or radiotherapy, use of ADT with the primary therapy, or presence of metastases and PSA level at ADT initiation.

Statins are administered widely in the United States for their clinically meaningful lipid-lowering properties. Most epidemiological studies have shown significant associations between statin use and decreased incidence of advanced prostate cancer, risk of recurrence after local treatment, mortality, and PSA levels relative to nonusers.

SLCO2B1 is an organic anionic transporter that allows a number of anticancer compounds and hormones to enter cells. Chief among its substrates is the adrenal androgen dehydroepiandrosterone sulfate (DHEAS), which is a precursor to more potent androgens. Among the potent androgens is dihydroxytestosterone (DHT), which binds to the androgen receptor in normal and cancer cells. In prostate cancer, expression of SLCO2B1 increases on progression from hormone-sensitive to castration-resistant disease.

Continued reliance of the tumor on androgen receptor signaling and residual androgens contributes to progression to castration-resistant prostate cancer (CRPC). In the study, Lauren C. Harshman, MD, of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and colleagues found that DHEAS and various statins compete for binding to the transporter SLCO2B1. They theorize that statins can competitively inhibit DHEAS uptake.

Given the biologic heterogeneity observed in prostate cancer, what becomes clear is that the ability of a therapy to thwart the development of lethal prostate cancer is more important than decreasing the overall incidence, wrote the authors.

The authors concluded that the mechanism through which statins exert their activity in prostate cancer is likely “multifactorial, including antiproliferative and proapoptotic effects.” The authors suggest that the most plausible mechanism may be attributed to a reduction in the tumor’s androgen stores through a combination of decreased availability of the cholesterol precursor required for de novo synthesis and decreased transport of existing precursor androgens such as DHEAS via competitive binding of SLCO2B1.

“These findings are preliminary, so I would not recommend that everybody start on statins to slow prostate cancer,” senior author Philip Kantoff, MD, chief of solid tumor oncology at the Dana-Farber Cancer Institute in Boston, said in a statement. Also, Kantoff cautioned that these findings apply only to men who have advanced prostate cancer that has relapsed after androgen deprivation therapy. “This does not speak to early-stage prostate cancer or whether statins are beneficial in preventing prostate cancer,” he said.