Prostate cancer (PC) represents the most frequently diagnosed malignancy and ranks as the second most common cause of cancer-related death among men worldwide (1). Castration-resistant prostate cancer (CRPC), which involves disease progression despite castrate levels of serum testosterone (<50 ng/dL), manifests as rising prostate-specific antigen (PSA), radiographic advancement, or symptom deterioration (2). As the terminal stage of PCa, CRPC is responsible for the majority of PCa-related deaths, with 10%–20% of patients developing CRPC within five years of initiating androgen deprivation therapy (ADT) (3). Although therapeutic strategies such as taxane-based chemotherapy (docetaxel, cabazitaxel), androgen receptor inhibitors (abiraterone, enzalutamide), and radiopharmaceuticals (radium-223) have been introduced, overall survival in CRPC remains limited, averaging 13–16 months (4–6). These findings underscore the need for reliable prognostic biomarkers to enhance risk stratification and inform clinical decision-making.

Recent studies suggest that systemic inflammation plays a crucial role in the progression of CRPC and its resistance to treatment (7). Chronic inflammation contributes to an immunosuppressive microenvironment, promotes angiogenesis, impairs DNA repair, and activates androgen receptor signaling (8). Among inflammatory markers, the platelet-to-lymphocyte ratio (PLR) has gained attention for its low cost, reproducibility, and clinical accessibility. PLR reflects both thrombocytosis, which supports tumor survival and metastasis (9), and lymphopenia, which indicates weakened antitumor immunity (10), thus offering a dual perspective on tumor-host dynamics.

In CRPC, elevated PLR is strongly associated with aggressive tumor behavior and unfavorable prognosis. Neuberger M et al. (2023) (11) demonstrated that high PLR independently predicted shorter OS in individuals treated with docetaxel. Similarly, Wang ZP et al. (2024) (12) reported that elevated PLR during abiraterone therapy was associated with reduced OS and PFS. These findings highlight PLR as a low-cost, accessible prognostic marker in the management of CRPC.

Previous meta-analyses on PLR in prostate cancer often lacked stage-specific stratification. For instance, Guo JN et al. (2018) (13) included five studies and found that elevated PLR was associated with poorer OS and PFS but did not differentiate CRPC from other stages. Salciccia S et al. (2022) (14) analyzed metastatic and non-metastatic cases separately and found no association between PLR and biochemical progression or mortality in metastatic disease. These inconsistent results reflect the limited and inconclusive evidence for PLR in CRPC, highlighting the need for stage-specific analyses. CRPC’s distinct inflammatory microenvironment may uniquely affect the prognostic value of PLR.

To address these limitations, we conducted a systematic review and meta-analysis focusing on CRPC to evaluate the prognostic value of PLR for OS and PFS. Subgroup and mechanistic analyses were performed to explore sources of heterogeneity and underlying biological mechanisms. This analysis provides the most comprehensive evidence to date supporting PLR as a standardized risk stratification tool in CRPC, offering insights to guide the development of future biomarker-driven therapeutic strategies.

In recent years, the association between systemic inflammatory responses and cancer prognosis has garnered increasing attention. The PLR, an integrative inflammatory marker, has emerged as a promising prognostic indicator due to its simplicity, low cost, and widespread availability. PLR has been shown to correlate strongly with patient survival in various solid tumors, including colorectal cancer (30), lung cancer (31), and endometrial cancer (32). However, in CRPC, the terminal stage of prostate cancer, the prognostic value of PLR remains controversial.

Findings from the meta-analysis of 13 studies involving 2,405 patients indicated that increased PLR was significantly linked to shorter OS in CRPC (HR = 1.62), while no significant association was observed with PFS. A prior meta-analysis by Guan YP et al. (2020) (33), based on only three studies, reported worse OS in metastatic CRPC patients with elevated PLR receiving abiraterone or enzalutamide. Compared to earlier studies that focused mainly on hormone-treated patients, our study includes more studies and a broader range of treatments, providing a clearer view of PLR’s stratification value in advanced CRPC. PLR appears to be a more consistent predictor of long-term outcomes like OS. At the same time, its association with short-term endpoints such as PFS may be influenced by treatment variability and tumor heterogeneity. This interpretation should be viewed with caution because only four studies reported PFS and the corresponding effect estimate was likely underpowered. By contrast, for overall survival we were able to include a larger number of CRPC studies and to perform rigorous subgroup and sensitivity analyses, so our study strengthens the evidence supporting the prognostic value of PLR in CRPC, particularly for OS.

Subgroup analyses provided new insights into the heterogeneous prognostic value of PLR in prostate cancer. Regionally, no significant association was found between PLR and OS in the Americas (HR = 2.38, p = 0.09), likely due to the limited statistical power resulting from a single study (n = 158) and biological variability associated with ethnic diversity. In contrast, higher PLR was consistently linked to poorer OS in both Asian (HR = 1.71, I² = 90%) and European (HR = 1.54, I² = 47%) populations, supporting its cross-ethnic applicability. The high heterogeneity, particularly in Asian cohorts, may reflect underlying biological complexity, including genetic variations that influence inflammatory thresholds, platelet activation, and lymphocyte function (34, 35). Healthcare disparities may also contribute. In developed countries like the U.S., widespread prostate cancer screening often identifies early-stage cases, while studies from developing regions include more advanced disease, potentially confounding the PLR–prognosis relationship (36, 37). In the treatment-based analysis, PLR showed no significant association with OS in the chemotherapy subgroup (HR = 2.75, p = 0.10). This may be due to the bone marrow-suppressive effects of docetaxel (38), which impairs both platelet and lymphocyte production by disrupting microtubule function and inducing hematopoietic stem cell arrest. These effects can lead to asynchronous cell count fluctuations, reducing PLR stability and interpretability (39). Similar hematologic toxicity profiles were reported in pivotal docetaxel trials in mCRPC, where neutropenia and other cytopenias were frequent (40, 41), supporting the notion that chemotherapy itself can distort inflammation-based ratios. Therefore, the null finding in the chemotherapy subgroup may reflect treatment-related hematologic interference rather than a true absence of prognostic value. Future studies should incorporate serial PLR measurements (baseline, on-treatment, and post-treatment) to better define its prognostic dynamics in docetaxel-treated CRPC.

Inflammatory responses in the tumor microenvironment are closely linked to cancer progression and metastasis (42). Platelets, as key effector cells, may drive CRPC progression through several mechanisms. They release VEGF and PDGF, promoting angiogenesis via endothelial receptor activation and supporting tumor growth and metastasis (43), with pro-angiogenic activity being strongly associated with bone metastases (44). Platelet-derived TGF-β1 also induces epithelial–mesenchymal transition (EMT) through the Smad2/3 pathway, enhancing tumor cell migration and invasion (45). In addition, circulating tumor cells (CTCs) can bind to platelets, forming protective complexes that shield them from NK cell–mediated cytotoxicity and facilitate vascular adhesion (46). In the tumor immune microenvironment, elevated PLR is often associated with reduced CD8⁺ T-cell counts (47), which are linked to poor prognosis in metastatic CRPC (10). Tumor-associated macrophages (TAMs) suppress CD8⁺ T-cell proliferation by secreting IL-10 and PGE2 (48, 49). Myeloid-derived suppressor cells (MDSCs) further impair antitumor immunity by depleting L-arginine via arginase-1 (Arg-1), leading to T-cell dysfunction (50).

The chronic inflammatory microenvironment drives tumor metastasis through several signaling pathways. IL-6/STAT3 activation enhances resistance to apoptosis and promotes cancer cell proliferation, invasion, and metastasis (51). The TNF-α/NF-κB pathway accelerates the tumor cell cycle and growth (52). Additionally, the COX-2/PGE2 axis suppresses immune responses and supports tumor stemness through receptor-mediated signaling (53). These immune–inflammatory pathways provide a plausible biological explanation for the association between elevated PLR and poorer outcomes in CRPC. In addition, about 20%–30% of metastatic or castration-resistant cases carry somatic or germline DNA damage response (DDR) alterations, with BRCA2 among the most frequent, and these changes are also associated with more aggressive disease (54–56). Because most included studies did not report such genomic data, we could not determine how much of the risk attributed to PLR overlaps with this unmeasured high-risk molecular subset, which should be clarified in genomically profiled cohorts.

This study has several limitations. First, although 13 studies were included, only three studies included patients treated with chemotherapy, and only four studies reported PFS, which reduces the statistical power of these subgroup analyses and may partly account for the non-significant findings. Second, most of the included studies were retrospective and used different PLR cut-off values and outcome definitions, so residual confounding and methodological heterogeneity cannot be excluded; moreover, inflammatory comorbidities such as chronic infections or autoimmune diseases were not reported in the original studies, so we were unable to assess their potential impact on PLR independent of tumor burden. Third, genomic information relevant to advanced prostate cancer was not reported in most primary studies, so we could not adjust for potentially important molecular prognostic factors. Finally, most cohorts originated from Europe and Asia, with limited representation from other regions, which may restrict the generalizability of our conclusions. Prospective, multicenter, genomically annotated studies with standardized and, ideally, longitudinal PLR assessment are needed to validate these results.

In summary, this meta-analysis confirms that elevated PLR is an independent adverse prognostic factor for OS in CRPC, with consistent findings in hormone therapy subgroups and European populations. Despite variability in cut-off values, PLR’s low cost and accessibility support its potential role in clinical risk stratification. Future studies should standardize measurement protocols and explore the combination of PLR with other markers, such as the neutrophil-to-lymphocyte ratio (NLR), to develop multiparametric prognostic models. Further investigation into PLR’s association with immunotherapy response is also warranted. These efforts could help shift PLR from a prognostic marker to a tool for guiding clinical decisions, advancing precision management in CRPC.

This meta-analysis confirms that PLR is a significant prognostic marker for OS in CRPC, with higher levels associated with shorter OS. However, its prognostic value was not significant among patients receiving chemotherapy or in American populations. Given the heterogeneity and limitations of retrospective studies, prospective multicenter research is necessary to validate these findings. Standardizing PLR measurement and investigating its interaction with emerging therapies such as PARP inhibitors and immunotherapy will be essential for refining its clinical applicability. Ultimately, incorporating PLR into prognostic models may facilitate early identification of high-risk patients and guide timely, targeted treatment.