Statins for Prostate Cancer: When and How Much?

In this issue of Clinical Cancer Research, Jeong and colleagues (1) reported results of a randomized double-blind placebo-controlled clinical trial, which tested low-dose atorvastatin for 1 year as adjuvant treatment after curative-intent radical prostatectomy in Asian men with high-risk prostate cancer. Primary end-point was 1-year biochemical recurrence (BCR), defined as PSA greater than 0.2 ng/mL in at least one measurement. Secondary endpoints were 5-year BCR and changes in serum lipids, testosterone, and sex-hormone binding globulin. No difference compared with placebo was observed in BCR end-points or steroid hormone levels. To our knowledge, this is the first randomized placebo-controlled trial comparing atorvastatin with placebo as adjuvant prostate cancer treatment after prostatectomy. Thus, authors are to be congratulated for this contribution.

This study demonstrates that long-term but low-dose adjuvant treatment with atorvastatin after prostatectomy has no benefit on occurrence of biochemical recurrence rate. So, should we forget about statins in context of prostate cancer? No, we should not. After all, there is a clear biological rationale for statins to be effective against prostate cancer. De novo cholesterol production, which is upregulated in prostate cancer cells, depends on the mevalonate pathway (Fig. 1). Statins inhibit 3-hydroxy-3- methylglutaryl-coA (HMG-CoA) reductase which converts HMG-CoA to mevalonic acid. Apart from cholesterol, mevalonate pathway also produces isoprenoid proteins such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, thus participating in regulation of several central cellular functions. Cholesterol itself is precursor for biosynthesis of all steroid hormones including androgens. As statins inhibit the whole mevalonate pathway, statin use leads to increased apoptosis, decreased cell proliferation, and modulation of lipid metabolism in prostate cancer cells. Lipid metabolism has been linked with development of castration resistance and tolerability of hypoxic tumor microenvironment. Statins may also interfere with solute carrier organic anion (SLCO)-encoded membrane transporters that have a role in androgen transportation across the cell membrane (2). Higher expression and genetic variation of SLCO transporters has been noted in prostate cancer. Thus, it is suggested that SLCO-mediated androgen transport has a role in prostate cancer progression and treatment responses. Interestingly, SLCO transporters also transport statins, thus providing a potential way for statins to access prostate cancer cells. Further, statins may inhibit uptake of adrenal androgens such as dehydroepiandrosterone sulfate (DHEAS) in prostate cancer cells via SLCO inhibition (3). Concordantly, we have recently shown atorvastatin to lower intraprostatic concentrations of adrenal androgens in men with prostate cancer (4).

Taking together, interfering with prostate cancer cells' lipid metabolism, cholesterol availability, and modulation of androgen transport with statins could in theory have marked effects against growth and survival of these cells.

Two previous clinical trials that tested high-dose statin use in neoadjuvant setting before prostatectomy suggested increased apoptosis and lowered tumor proliferation activity (5, 6), though not inconclusively as some findings were observed only in subgroup analyses. Epidemiologic evidence also supports that statin use delays prostate cancer progression, as studies consistently report lowered risk of prostate cancer–related death among statin users compared with nonusers.

The negative result of this study is not unexpected for 2 reasons. Firstly, the dose of the atorvastatin was low, only 20 mg daily. Both of the above-mentioned clinical trials testing neoadjuvant atorvastatin and fluvastatin before prostatectomy (5, 6) used high-dose statin intervention of 80 mg daily suggesting beneficial impact on prostate-cancer cell proliferation after minimum use of 28 days (5) and apoptosis (6). Furthermore, both trials demonstrated detectable statin concentration in the prostate tissue after prostatectomy. The 20-mg dose of atorvastatin used by Jeong and colleagues is much lower, and it is unknown whether it is enough to reach prostatic tissue at sufficient concentrations. Commonly, atorvastatin is used with the daily dose of 10 to 80 mg for management of hypercholesterolemia or cardiovascular disease. Thus a 20-mg dose is low even for the primary indication of statin use, and may not even lower cholesterol in all participants, even though a drop in mean cholesterol and LDL was reported in the atorvastatin arm.

Secondly, adjuvant setting after prostatectomy is not an optimal clinical scenario to study statins in prostate cancer, and biochemical recurrence after prostatectomy is not always a clinically relevant endpoint. Based on recent systematic review (7) adjuvant treatment with docetaxel or androgen deprivation therapy (ADT), both routinely used treatments in advanced prostate cancer, have no clear benefit on delaying biochemical recurrence after prostatectomy, even though both provide survival benefit at advanced stages of the disease. Therefore, it is not surprising that low-dose statin intervention does not affect this endpoint, either.

In pharmacoepidemiologic studies statin use has been consistently associated with lowered prostate cancer–specific mortality, thus a more suitable primary endpoint for future studies would be mortality rather that biochemical relapse (6). Furthermore, in the trial of Jeong and colleagues (1) 10% of the participants in both arms had PSA levels greater than 0.2 ng/mL already at the baseline which raises a question about the suitability of the selected primary endpoint in this study.

Certain subgroups within prostate cancer patients have been suggested to benefit more from statin use than others. These include men with high-grade tumors (5). Also biomarker-based classifications for identification of statin-sensitive tumors have been proposed (8). In the current study the patient population was limited to high-risk patients, defined by presence of at least 1 of the following factors: tumor growth beyond the prostate capsule, invasion of the seminal vesicles (T3 stage), positive surgical margins, or Gleason score 8 or greater. This combination of stage and grade for definition of high-risk likely also contributes to heterogeneity compared with previous neoadjuvant trials, where PSA was lowered by statin use only in the group of men with ISUP score 3 or higher tumors (5). In the current study by Jeong and colleagues (1) ISUP Gleason score did not modify the risk of BCR by statin use. Nevertheless, this study was not powered for these subgroup analyses.

Based on epidemiologic studies, statins may be most beneficial during androgen-targeted therapy, which is logical given that cholesterol is a precursor for androgen production. Statin use has been associated with prolonged treatment responses to ADT, as well as to drugs abiraterone and enzalutamide which target androgen production and signaling. Therefore, future clinical statin studies in prostate cancer should examine the drug group in combination with ADT. Suitability of this patient group for statin studies is further supported by elevated cardiovascular morbidity among ADT users.

In conclusion, we applaud the efforts of Jeong and colleagues for showing that low-dose atorvastatin treatment for 1 year after prostatectomy has no impact on delaying biochemical recurrence in Asian men with high-risk prostate cancer. This shows that adjuvant treatment after prostatectomy is not the optimal clinical scenario to test efficacy of statin treatment, and higher doses of statins are probably needed to affect prostate cancer. As statin use has been associated with decreased prostate cancer–specific mortality among men on ADT, future trials on efficacy of statin use in prostate cancer should focus on patients with advanced cancer who are treated with ADT or new-era antiandrogens. This also opens the possibility to study clinically meaningful endpoints like survival and quality of life.

T.J. Murtola reports personal fees from Janssen, Ferring, Astellas, Sanofi, Merck, and Novartis outside the submitted work. No disclosures were reported by the other author.