Bladder cancer (BCa) ranked as the fourth most prevalent cancer in men in 2023, accounting for approximately 6% of newly diagnosed cancers and 4% of cancer-related deaths (Lopez-Beltran et al., 2024). Furthermore, bladder cancer was reported to incur the highest expense per patient of all cancers (Mossanen and Gore, 2014). Upon initial diagnosis, between 70% and 75% of BCa patients are found to have non-muscle-invasive bladder cancer (NMIBC), while 20%–25% of patients are diagnosed with muscle-invasive bladder cancer (MIBC), and an additional 5% of patients present with metastatic disease (Lopez-Beltran et al., 2024). Although NMIBC often presents with a more favorable outlook, with many cases managed through chronic monitoring due to a high recurrence rate (Lenis et al., 2020), the situation shifts dramatically with MIBC progression. This transition marks a pivoting toward a more aggressive disease spectrum, wherein the 5-year survival rates decline to approximately 50% (Wissing et al., 2019), thus necessitating multimodal and invasive treatment strategies. Given the grim outlook associated with MIBC, treatment strategies encompass a comprehensive approach that includes radical surgery, radiotherapy, and chemotherapy. Despite these measures, approximately half of the affected individuals experience metastasis and succumb to the disease within 3 years (Fan et al., 2021). Consequently, the implementation of early detection techniques and continuous monitoring of patient prognosis are crucial for decreasing the mortality rates associated with bladder cancer (BCa).

Numerous in vitro and in vivo studies have underscored the significance of androgen receptors (ARs) in the onset, progression, and relapse of BCa, as well as its resilience against standard treatments, including radiotherapy, chemotherapy, and Bacillus Calmette-Guerin therapy (Kourbanhoussen et al., 2021; Ide and Miyamoto, 2021; Costa et al., 2020; Koti et al., 2020; Luna-Velez et al., 2021; Deng et al., 2021; Ide et al., 2018; Tripathi and Gupta, 2020). 5-Alpha reductase inhibitors (5-ARIs) are used as androgen suppression therapy (AST) that targets and effectively impedes the production of dihydrotestosterone (DHT), the foremost endogenous activator of androgen receptors (ARs). Recent clinical studies indicated that attenuating androgenic signaling (Morales et al., 2016) could impact the behavior of BCa. However, whether 5-ARIs affect the prognosis and risk of BCa is still unclear (Sathianathen et al., 2018; Wissing et al., 2019; Wissing et al., 2021; Wang et al., 2020; Dekalo et al., 2023). Evidence from preclinical research indicated that the efficacy of antiandrogen drugs against BCa varies (Imada et al., 1997). Based on population data, Dekalo’s retrospective cohort study explored the associations between the use of 5ARIs, BCa occurrence, and related mortality. The study found that the intake of finasteride but not dutasteride was related to a decrease in BCa risk (Dekalo et al., 2023). The findings suggest that a significant variation in outcomes observed across prior studies can be attributed to the simultaneous examination of 5-ARIs and androgen deprivation therapy (ADT), as well as the effects of finasteride and dutasteride. Numerous prior analyses have highlighted a potential link between AST and BCa (Kim et al., 2020; Creta et al., 2021; Xiang et al., 2021). However, there is a notable gap in research specifically examining the influence of finasteride on BCa risk and prognosis. Thus, as new research emerges, an updated synthesis of the findings is needed.

The purpose of our study was to synthesize existing data and deliver an in-depth systematic review of the effects of finasteride on the occurrence of BCa and patient prognosis. This research findings should significantly enhance our comprehension of the risk and prognostic factors of BCa and present strategies for its prevention or treatment.

The investigation of 5-ARI, as crucial component of ASTs utilized in the clinical management of benign prostatic hyperplasia (BPH) (Kim et al., 2016), has recently shifted toward investigating the potential of 5-ARIs in a new therapeutic context—addressing the incidence of BCa. However, the conclusions are inconsistent (Zhu et al., 2021; Dekalo et al., 2023; Sathianathen et al., 2018). We conducted a meta-analysis incorporating data from several studies to elucidate the specific influence of finasteride treatment on BCa outcomes. Specifically, individuals with a history of finasteride use exhibited an HR of 0.75 (P = 0.001) compared to nonusers, suggesting a 25% reduction in BCa risk.

Some potential mechanisms may explain our findings. 1) The impact on the AR signaling pathway. As a member of the 5-ARI class of drugs, finasteride could influence AR signaling, which had been implicated in several key genomic events, including the induction of DNA breaks, alterations in chromosomal structure, and the inhibition of uridine 5′-diphospho-glucuronosyltransferase activity, a pivotal enzyme in the detoxification process (Lin et al., 2009; Izumi et al., 2013). These findings suggest that AR signaling may contribute to carcinogenesis by compromising genomic stability and impairing the cellular capacity to detoxify carcinogens. Meanwhile, analysis of The Cancer Genome Atlas (TCGA) data revealed modifications in 5-AR genes at both the DNA and RNA levels, characterized by gene amplification and elevated mRNA expression, which underscores the genetic basis for targeting AR signaling in BCa (Chen et al., 2017). This dual effect of 5-ARIs offers a promising avenue for BCa management, suggesting a direct impact on AR signaling as a mechanism of action. 2) Interference with the tumor microenvironment. As BCa is a heterogeneous malignancy characterized by distinct immune subtypes and differences in the tumor immune microenvironment landscape, various components, including tumor cells, stromal cells, immune cells, and the extracellular matrix, have prognostic surveillance. A previous study indicated that finasteride could potentially inhibit the expression of Insulin-like Growth Factor 1(IGF-1) by suppressing the activity of c-JUN within fibroblasts in benign prostate tissue, leading to a reduction in the synthesis and secretion of IGF-1 (Wang et al., 2017). IGF-1 has been found to promote the proliferation of prostate cancer cells and inhibit apoptosis (Wissmiller et al., 2023). Another study found that finasteride reduced the secretion of CCL5 by CD8⁺ T cells by upregulating the cGMP/PKG/p6 5 signaling pathway (Jin et al., 2019). CCL5 is believed to promote the proliferation and metastasis of bladder cancer through the JAK2/STAT3 signaling pathway (Shen et al., 2023), which might suggest the reliability of finasteride in reducing the occurrence of BCa from the perspective of the immune microenvironment. 3)Produce crosstalk between tumors and microorganisms. In contemporary scientific discourse, inflammation is regarded as a major contributing factor to carcinogenesis, with the microorganism being recognized as an integral element in this process (Elinav et al., 2013). Recent research findings indicated that finasteride may possess anti-inflammatory properties that reduce multiple inflammatory factors, including NOS2, NOX4, and COX2, in murine models of BPH (Lee et al., 2023). A separate study observed that the cessation of finasteride intake could result in the onset of intestinal inflammation in adult male mice, which was characterized by elevated expression levels of interleukin-6β, tumor necrosis factor-α, and other pro-inflammatory cytokines (Diviccaro S et al., 2022). Furthermore, microbial imbalance within the bladder could contribute to the development of BCa. Nardelli and colleagues examined the relationship between the urinary microbiome and bladder cancer (Nardelli et al., 2024). They found an increased abundance of bacteria from the Porphyromonas genus, particularly Porphyromonas somerae, in urine from BCa patients. Of particular interest is the association of P. somerae with the progression of endometrial cancer, where it has been implicated in the promotion of carcinogenesis through mechanisms including the induction of inflammation, the modulation of host cell functions, and the enhancement of oxidative stress. Additionally, droplet digital Polymerase Chain Reaction and next-generation sequencing methodologies showed that the presence and abundance of P. somerae in urine samples from BCa patients were significantly higher than in urine samples from the control group (Russo et al., 2024), which support that Porphyromonas somerae has the potential to serve as a distinctive microbiome marker for BCa. 4)The interaction between androgens, estrogens, and the immune system. 5-ARIs have been shown to increase estrogen levels in the serum of males, which, combined with significant changes in local sex steroid concentrations, may enhance local immune responses against tumor cells (Shibata et al., 2017; Kristal et al., 2012). The incidence of bladder cancer exhibits a gender correlation—with a higher incidence rate in males. In males, the loss of the Y chromosome (LOY) occurs at a high rate of up to 40% (Minner et al., 2010). A study indicates that the LOY can induce terminal exhaustion of CD8⁺ T cells, leading to immune evasion in bladder cancer. Concurrently, the loss of the Y chromosome increases the sensitivity of bladder cancer patients to anti-PD1 immune checkpoint inhibitor therapy (Abdel-Hafiz et al., 2023). There are articles explaining that, given urothelial carcinoma’s response to checkpoint inhibitors, the modulation of sex hormone levels by 5-ARIs could synergize with immunotherapeutic strategies to counteract tumor-induced immune suppression (Bellmunt et al., 2017).

We conducted several subgroup and leave-one-out sensitivity analyses to mitigate the potential confounding factors associated with heterogeneity. First, the subgroup analysis by study region indicated the significant impact of finasteride on the decreased occurrence of BCa in patients in both North America and Asia, which indicated that ethnicity could be a significant factor influencing the BCa risk influence of finasteride. This emphasizes the importance of considering ethnic diversity in assessing the efficacy and safety profile of the drug. Zhu proposed that polymorphisms within the AR gene, which activates ARs independent of DHT binding, may contribute to the observed variance (Zhu et al., 2021). This insight underscores a potential genetic mechanism that could influence the response to therapies targeting the androgen pathway. Further research is warranted to explore the mechanisms behind these variations and to determine whether specific ethnic populations may benefit more or face greater risks from finasteride therapy. Second, subgroup analysis by type of research, average age of patients, and sample size was conducted to verify their impact on the study findings. The results indicated that finasteride treatment reduced the incidence of BCa by 28% in a retrospective cohort subgroup, by 16% in a case-control subgroup, by 20% in a subgroup >65 years old, and by 26% in sample size >10,000 subgroup. Meanwhile, we adopted a leave-one-out sensitivity analysis to mitigate this effect and assess the solidity of our conclusions, reinforcing the robustness of our study.

An increasing number of studies have focused on the impact of finasteride on the prognosis of patients with BCa. Garg’s research indicated a positive correlation between the use of finasteride and enhanced OS among patients diagnosed with NMIBC (Garg et al., 2023). Another observation by McMartin et al. (McMartin et al., 2019) suggested that 5-ARIs might also confer beneficial biological effects on individuals with MIBC. Contrary to previous meta-analysis findings (Creta et al., 2021) that indicated a lower risk of BCa recurrence with 5-ARI treatment, our study found that the finasteride treatment did not significantly improve OS, CSS, or RFS, which collectively indicated that finasteride did not appear to affect survival outcomes or the likelihood of cancer recurrence. Possible explanations for these findings include differences in the follow-up periods in the included studies, particularly the restricted number of cases with a follow-up duration exceeding 10 years. Concurrently, the limited number of studies restricted us from stratifying risk factors related to BCa, such as T stage, pathological grading, lymph node invasion, or distant metastasis. We also refined the inclusion criteria by omitting two studies due to their lack of finasteride usage, aiming to enhance the accuracy of our conclusions. The differences in findings between our analysis and prior studies may stem from these methodological adjustments and the inclusion of new data, highlighting the evolving nature of medical evidence.

Several study limitations should be considered. First, although we did not restrict the language of the included studies and expanded our literature search to unpublished trials and abstracts, potential bias could not be avoided. Second, although we performed subgroup and sensitivity analyses to try to control for potential confounding factors, the efficacy of mitigating confounding factors that may interfere with the application of research findings was limited by the number of included studies. Third, the absence of detailed information on tumor characteristics, including pathological grade or T stage, limited our understanding of the impact of finasteride on BCa in our pooled analysis. Fourth, the heterogeneity among the included samples, possibly due to the varied inclusion of 5-ARIs, may have obscured the true association between finasteride use and BCa outcomes. Lastly, factors such as the dose of finasteride used and the duration of administration were not be done by subgroups analysis due to the limited number of samples included. Chen et al. (2017) categorized 5-alpha-reductase inhibitor (5ARI) usage into three tiers by cumulative defined daily doses (cDDD) as 0, 1 to 179, and over 180 which is calculated as the sum of dispensed DDD over time, with DDD being the assumed average daily maintenance dose of a drug used for its main indication in adults, and reported that patients with daily doses >180 had a lower propensity for BCa development. Meanwhile, Snir Dekalo’s study (Dekalo et al., 2023) revealed a significant protective effect of 5ARIs after a minimum of 2 years of exposure. These findings emphasize the need for further research to assess the long-term effects of continuous finasteride therapy or dose-response relationship of 5ARI with BCa risk.

The findings of this study, which indicate a significant effect of finasteride in preventing the occurrence of BCa, as well as high incidence and mortality rates, support the feasible of finasteride chemoprevention trials in populations at high risk for bladder cancer. The specific mechanisms of finasteride in preventing BCa are currently unclear; hence, further molecular biology experiments should be performed. A large-sample, multicenter, prospective study of finasteride uptake should be conducted. Due to the lack of detailed data on cancer grading, staging, or histology in existing studies, there is an expectation that future studies will provide more detailed clinical reports to assist researchers in further investigating bladder cancer. Regular long-term follow-up and detailed subgroup stratification will help to assess the true value of finasteride in preventing the development of BCa and provide new ideas for future integrated treatment, including postoperative bladder perfusion therapy for NMIBC, preoperative neoadjuvant chemotherapy for MIBC, and adjuvant chemotherapy for advanced metastatic BCa.

Our comprehensive review and meta-analysis included 13 studies that evaluated the impact of finasteride on the risk and clinical outcomes of patients with BCa. The analysis indicated that finasteride contributes positively to reducing the incidence of BCa. Our subgroup analysis results suggested that finasteride shows a significant potential for preventing BCa across different regions. No notable differences were observed in OS, CSS, or RFS between the finasteride group and controls. Future research should include rigorously designed prospective studies that account for prevalent confounding variables to corroborate these findings.