Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. A population-based cohort study

Abstract

Purpose Statins' cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins' effect on prostate cancer prognosis among patients treated with ADT. Materials and methods Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. Results During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65-0.82) and prostate cancer death (HR 0.82; 95% CI 0.69-0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76-1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96-1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85-1.24) were not associated with prostate cancer death, without dose dependency. Conclusion Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.

The Roles of Tumor-Associated Macrophages in Prostate Cancer

“…erefore its application is expected to extend survival after ADT. A recent report shows statins, known to decrease systemic cholesterol levels, significantly improve the benefits of ADT in patients [189]. ese agents reduced the availability of circulating cholesterol for ingestion by TAMs and its transfer towards neighboring tumor cells during ADT, possibly delaying the onset of CRPC.…”

Statins and prostate cancer—hype or hope? The epidemiological perspective

“…However, tumour progression inevitably occurs in spite of low availability of circulating androgens through a variety of documented mechanisms including intratumoral androgen synthesis from cholesterol [56]. As such, it has been hypothesised that statins may synergise with ADT by blocking accumulation of intratumoral cholesterol thereby reducing the substrate for de novo androgen synthesis within the prostate [57]. Given that more advanced tumours upregulate enzymes necessary for de novo androgen synthesis [58][59][60], it may be that statins have a stronger effect in later-stage tumours, enriched in the context of salvage ADT.…”

“…Indeed, inverse associations reported by the various observational studies completed to date (Table 1) appear slightly stronger among patients receiving salvage ADT, typically administrated later during the disease course compared to primary ADT. Among studies where the majority were using salvage ADT, estimates for statin use in association with prostate cancer-specific mortality ranged from HR 0.65 (95% CI 0.48-0.97) [61] to HR 0.86 (95% CI 0.69-1.07) [11], whereas among studies in the context of majority primary ADT, estimates ranged from HR 0.82 (95% CI 0.69-0.96) [57] to HR 0.98 (95% CI 0.72-1.32) [62]. These estimates could support a biological mechanism or be the result of greater difficulty with controlling time-varying confounding in settings of salvage ADT, where data on patient and tumour characteristics are typically known only at diagnosis.…”

“…With a view to understanding which point in clinical progression that the tumour may be most sensitive to statins, a number of studies reporting lower prostate cancer-specific mortality in statin users (Table 1) performed secondary analyses stratified by tumour features. Peltomaa and colleagues found no difference in the association between post-ADT statin use and prostate cancerspecific mortality when stratified by tumour risk group [57]. Anderson-Carter et al reported similar associations between statin use and outcomes when they restricted to men with higher PSA (>10 ng/ml) relative to the entire cohort [63].…”

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

“…All the studies were published between 2010 and 2021, with at least 6 score of NOS results. Among these studies, 7 studies were conducted in the USA [20,23,24,28,37,41,42], 4 in Canada [21,22,29,40], 4 in China [25,26,31,36], 4 in Finland [19,27,32,34], 1 in Italy [30], 1 in Denmark [33], 1 in Germany [35], 1 in the UK [38], and 1 in Norway [39]. 18 studies reported the association between statin use and PCMS, whereas 17 studies examined ACM.…”