Assessing the clinical outcomes of immunotherapy and docetaxel combinations in metastatic castration-resistant prostate cancer: a meta-analysis

Abstract

Background

Despite breakthroughs in treatment, metastatic castration-resistant prostate cancer (mCRPC) continues to pose a substantial problem. This meta-analysis sought to assess the efficacy and safety of immunotherapy-chemotherapy combinations in mCRPC.

Methods

A thorough search of ClinicalTrials.gov, Embase, PubMed, SCOPUS, and Web of Science was performed to retrieve randomised controlled trials (RCTs) published between January 2000 and July 2024. The primary outcomes included overall survival (OS), progression-free survival (PFS), PSA response rate, time to PSA progression, and severe adverse events (SAEs). Data were aggregated using fixed-effect or random-effects models dependent on heterogeneity.

Results

Four RCTs involving 2,289 participants were included. The pooled results showed no statistically significant advantage of immunotherapy-chemotherapy combinations over placebo or docetaxel alone for OS (HR = 0.95; 95%CI: 0.79–1.14; P = 0.56), PFS (HR = 0.93; 95%CI: 0.80–1.07; P = 0.32), PSA response rate (RR = 0.99; 95%CI: 0.66–1.49; P = 0.96), time to PSA progression (HR = 1.01; 95%CI: 0.90–1.14; P = 0.85). The risk of SAEs was also not significantly different between the intervention and control groups (RR = 0.95; 95%CI: 0.71–1.29; P = 0.76).

Conclusion

Existing findings do not suggest a significant advantage of immunotherapy-chemotherapy combos over chemotherapy alone in mCRPC. However, the small number of trials and study heterogeneity call for caution in interpretation. Further high-quality RCTs are required to determine the role of these combinations in mCRPC treatment.

Background

Prostate cancer (PCa) is the second most prevalent malignancy, which accounts for the majority of cancer-related mortality in males, with an annual report of 1,467,854 new cases and 397,430 deaths in 2022 [1]. While localized PCa is effectively managed with treatments such as radical prostatectomy, brachytherapy, and radiation therapy, advanced stages often require Androgen Deprivation Therapy (ADT) to inhibit testosterone-driven tumour growth [2]. Nonetheless, resistance mechanisms, including intratumoral androgen production and aberrations in pathways such as PI3K and NF-κB, lead to the development of metastatic castration-resistant prostate cancer (mCRPC) within 18–24 months [3, 4].

For decades, taxane-based chemotherapy, particularly docetaxel combined with prednisone, has been the cornerstone of treatment for mCRPC, demonstrating both cytotoxic and immunomodulatory effects [5, 6]. Docetaxel enhances tumour antigen presentation, downregulates immunosuppressive T cells, and modulates inflammatory cytokines, transforming the immunosuppressive tumour microenvironment into an immune-responsive state [6, 7]. Despite its benefits, the efficacy of docetaxel is often limited by the development of resistance, necessitating new therapeutic approaches [8]. Platinum compounds have also shown potential in treating mCRPC, with the carboplatin-cabazitaxel combination emerging as a recommended option in some instances [9]. Current research reports positive preliminary results for platinum-based therapy in mCRPC, with PSA response rates ranging from 7.7% to 95% and overall survival improvements ranging from 8 to 26.6 months [10].

Immunotherapy inhibiting PD-1/PD-L1 pathways and CTLA-4 has improved the treatment landscape for several cancers by eliciting durable clinical responses [11]. However, in mCRPC, limited CD8 + T cell infiltration, regulatory T cells and myeloid-derived suppressor cells define the immunosuppressive tumour microenvironment that reduces the effectiveness of checkpoint inhibitors as monotherapies [12]. Emerging evidence suggests that combining immunotherapy with chemotherapy could overcome these challenges by leveraging the immunomodulatory effects of agents like docetaxel, which prime the immune system and potentially enhance the therapeutic impact of checkpoint inhibitors [11].

Preliminary clinical trials have reported promising results with chemotherapy-immunotherapy combinations, including improvements in overall survival (OS) and progression-free survival (PFS) and manageable safety profiles [13,14,15,16]. Yet, comprehensive evidence of these combinations’ efficacy and safety in mCRPC is lacking. Thus, this study aims to evaluate the effectiveness and safety of taxane and platinum-based chemotherapies combined with immunotherapy in mCRPC by synthesising data from randomised controlled trials.

Materials and methods

Search strategy

We systematically searched ClinicalTrials.gov, Embase, PubMed, SCOPUS, and Web of Science to retrieve studies published between January 2000 and July 2024. The search strategy employed an extensive array of MeSH terms, including terms related to immunotherapy (e.g., “immunotherapy,” “immune checkpoint inhibitors,” “PD-1 inhibitors,” “CTLA-4 inhibitors,” “Pembrolizumab,” “Nivolumab,” “Durvalumab,” “Camrelizumab,” “Atezolizumab,” and “Ipilimumab”), chemotherapy (e.g., “chemotherapy,” “docetaxel,” “cabazitaxel,” “paclitaxel,” “cisplatin,” “carboplatin,” and “oxaliplatin”), and disease-specific terms such as “metastatic castration-resistant prostate cancer” and “mCRPC.” Additionally, terms related to outcomes (e.g., “efficacy,” “overall survival,” “progression-free survival,” “safety,” “adverse events,” and “tolerability”) and study design (e.g., “randomised controlled trials”) were included to refine the search. Boolean operators were applied to combine terms, and database-specific filters were used where available.

Eligibility criteria

Studies were included if they investigated combinations of immunotherapeutic and chemotherapeutic agents in patients with metastatic castration-resistant prostate cancer (mCRPC), reported outcomes related to efficacy (e.g., OS, PSA, and PFS) and safety (e.g., adverse events) were randomised controlled trials (RCTs), and were published in English with accessible full texts. Exclusion criteria included studies focusing on therapeutic strategies other than immunotherapy or chemotherapy combinations, those involving populations outside the scope of mCRPC, and articles categorised as systematic reviews, meta-analyses, observational studies, scoping reviews, conference abstracts, or letters. Duplicate publications or studies lacking full-text availability were also excluded.

Data extraction

HR and HKK independently extracted data to ensure accuracy and minimise bias. The extracted information included study authorship, year of publication, and geographic location. Additionally, data on sample size, patient demographics, and treatment regimens, including the doses of immunotherapy and chemotherapy, were recorded. Primary and secondary outcomes (OS, PFS, PSA response, time to PSA progression and serious adverse events) were also extracted. Any author disagreements were handled through discussion or judgment by a third author.

Risk of bias assessment

The included studies’ potential for bias was evaluated using the Cochrane Risk of Bias (RoB 2.0) methodology. This tool assesses bias in five areas: (1) randomisation procedure, (2) deviations from planned treatments, (3) missing outcome data, (4) outcome measurement, and (5) choice of the stated result. Each domain was given a low, high, or some concerns risk level based on predetermined criteria. HR and IR separately evaluated their degree of bias; any differences were settled by AS using either adjudication or discussion.

Statistical analysis

Statistical analyses were conducted using RevMan software (version 5.3). The hazard ratio (HR) with the 95% confidence interval (CI) was used as the efficacy effect estimate for continuous outcomes (OS, PFS, Time to PSA). On the other hand, categorical outcomes, including PSA response rates and adverse events, were analysed using risk ratios. A p-value of < 0.05 was considered statistically significant. Heterogeneity among studies was assessed using the Cochran Q test and the I2 statistic, with I2 values > 50% indicating substantial heterogeneity. Depending on the level of heterogeneity, a fixed-effects model was applied for low heterogeneity, while a random-effects model was used for high heterogeneity. Forest plots were generated to represent the pooled estimates and visually assess consistency across studies. A funnel plot could not be created due to the limited number of included studies.

Results

Study selection

We identified records from various databases and registers, including Web of Science (n = 64), SCOPUS (n = 57), Embase (n = 138), PubMed (n = 273), and ctc.gov (n = 20). After removing 137 duplicate entries, we screened 415 records. Of these, 277 were excluded as they comprised reviews, commentaries, or case reports. Subsequently, 138 reports were assessed for eligibility, with 133 excluded for various reasons: 13 were outside the scope of the review, 3 were ongoing trials, 3 lacked reported results, 3 involved the wrong population, 109 used inappropriate interventions, and 3 were single-arm studies. Four RCTs were included in the review [17,18,19,20]. The study selection process is presented using a PRISMA flowchart (Fig. 1).

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Risk of bias assessment

The quality of the studies included was assessed with the ROB2 tool. Three trials [18,19,20] demonstrated a low risk of bias across allocation concealment, outcome assessment, random sequence generation, and selective reporting (Fig. 2). In contrast, the Randomized Phase II trial [17] showed a high risk of bias in several domains. Specifically, inadequate blinding of participants and personnel led to performance bias and incomplete blinding of outcome assessments, increasing the risk of detection bias. Additionally, the trial had issues with allocation concealment and missing outcome data, categorised as unclear. Despite these variations, all included studies adhered to standardised outcome measures, such as RECIST 1.1 and PSA levels, ensuring consistency in data collection and outcome evaluation.

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Characteristics of included studies

The articles included were published from 2015 to 2024. Two trials were Phase 2 RCTs [17, 18], and two were Phase 3 RCTs [19, 20]. The trials were carried out in the United States [17], Europe [19], and Denmark [18], with one in multiple countries [20]. Various immunotherapeutic strategies involving different immune checkpoint inhibitors, such as dendritic cell-based vaccines [18, 19], Pembrolizumab [20], and Granulocyte–macrophage colony-stimulating factor (GM-CSF) [17], have been documented in the studies included. Nonetheless, the use of docetaxel as a chemotherapeutic drug has remained consistent across all the studies. Table 1 shows the attributes and characteristics of the included studies. Table 2 summarises the key findings from the four clinical studies: OS, PFS, and time to PSA progression.

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Overall survival

Three clinical trials [17, 19, 20], with 1354 patients in the experimental and 935 patients in the control group, reported the effect of interventions compared with a placebo on overall survival. The test for heterogeneity indicated moderate heterogeneity among the studies (I2 = 51%, P = 0.13). The pooled results showed no statistically significant advantage of the intervention over placebo, with a combined HR of 0.95 (95% CI: 0.79–1.14; Z = 0.58, P = 0.56). Individual study estimates ranged from a potential benefit in Aggarwal et al. [17] (HR = 0.49, 95% CI: 0.22–1.09) to comparable effects in Petrylak et al. [20] (HR = 0.92, 95% CI: 0.78–1.09) and Vogelzang et al. [19] (HR = 1.04, 95% CI: 0.90–1.20) (Fig. 3).

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Progression-free survival

Two clinical trials assessed the PFS of patients treated with pembrolizumab [20] and DCVAC [19]. The test for heterogeneity indicated limited heterogeneity between the studies (I2 = 42%, P = 0.19). The pooled results demonstrated no statistically significant advantage of the intervention over placebo, with a combined HR of 0.93 (95% CI: 0.80–1.07; Z = 1.00, P = 0.32). Individual study estimates varied slightly, with Petrylak et al. [20] showing a potential benefit (HR = 0.85, 95% CI: 0.71–1.02) and Vogelzang et al. [19] reporting a near-null effect (OR = 0.99, 95% CI: 0.86–1.14), though neither result was statistically significant (Fig. 3).

Prostate specific antigen response rate

Three clinical trials assessed the intervention’s effect on PSA, including 508 participants in the treatment group and 518 in the control group [17, 18, 20]. The total number of events was 227 in the treatment group and 237 in the control group. The pooled analysis showed a relative risk (RR) of 0.99 (95% CI: 0.66–1.49; Z = 0.05, P = 0.96), indicating no significant difference between the intervention and control groups. The test for heterogeneity showed moderate variability among the studies (I2 = 46%, P = 0.16). Given the moderate heterogeneity, a random-effects model was applied (Fig. 4).

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Time to prostate-specific antigen progression

Two clinical trials evaluated the effect of interventions compared with a placebo on time to Prostate-Specific Antigen Progression [19, 20]. The test for heterogeneity indicated no significant heterogeneity between the studies (I2 = 0%, P = 0.33). The pooled results showed no statistically significant advantage of the intervention over placebo, with a combined HR of 1.01 (95% CI: 0.90–1.14; Z = 0.19, P = 0.85). Individual study estimates ranged from a slight potential benefit in Petrylak et al. (HR = 0.96, 95% CI: 0.82–1.12) to a modest trend towards harm in Vogelzang et al. (HR = 1.08, 95% CI: 0.91–1.29). However, neither result reached statistical significance (Fig. 4).

Serious adverse event

Three clinical trials [18,19,20] evaluated the intervention’s SAE across 2,198 participants, including 1,285 in the treatment group and 913 in the control group. The total number of events was 453 in the treatment group and 348 in the control group. The studies reported a pooled effect estimate (RR = 0.95, 95% CI: 0.71–1.29; Z = 0.31, P = 0.76), indicating no statistically significant difference between the intervention and control groups (Fig. 5).

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Discussion

The discovery of vaccine immunotherapy and immune checkpoint inhibitors has revolutionised therapeutic strategies for several metastatic cancers, including colorectal, non-small cell lung, breast, and prostate cancers, through agents targeting tumorigenesis pathways [11]. While numerous meta-analyses have highlighted the role of immunotherapies and immune checkpoint inhibitors as standalone treatments [21,22,23], the role of immunotherapy combined with docetaxel remains an area of active investigation in metastatic castration-resistant prostate cancer (mCRPC).

Although the immunotherapies included in our analysis; DCVAC, GM-CSF, and pembrolizumab differ mechanistically, they all aim to enhance antitumour immunity. DCVAC activates T cells via tumour antigen-loaded dendritic cells; GM-CSF promotes immune cell recruitment; and pembrolizumab restores T-cell function by blocking PD-1–mediated suppression. This mechanistic diversity adds complexity to pooled analysis, but reflects a shared therapeutic goal. Nonetheless, given the scarcity of large-scale RCTs evaluating individual immunotherapy strategies in mCRPC, our objective was to assess whether the general approach of combining immune modulation with chemotherapy confers clinical benefit.

Accordingly, we present a pooled estimate of 2,304 patients with mCRPC from four RCTs [17,18,19,20] while discussing individual agents separately. Despite substantial heterogeneity in several analyses, the combined data did not demonstrate a statistically significant benefit of immunotherapy with docetaxel over placebo or docetaxel alone.

Few trials have previously examined the clinical conditions of mCRPC using docetaxel-based treatment in conjunction with viral vector or dendritic cell (DC) based cancer vaccines [24,25,26]. A fraction of patients treated with this combination treatment have been shown to have peripheral immunological responses and clinical benefits. However, direct comparisons with other research are still circumscribed because of the lack of a randomised control group, different treatment methods, and often small study sizes. The absence of consistent immune surveillance procedures in the clinical context makes it even more challenging to characterise biomarkers that predict clinical success. Additionally, in Arlen et al.’s investigation [25] Antigen-specific immune surveillance relied on peripheral blood mononuclear cells (PBMCs) primed with antigen-presenting cells pulsed with peptides or peptides alone [26], further complicating direct comparisons.

Despite these challenges, Dendritic cell (DC) vaccines, such as Sipuleucel-T, have shown survival benefits in mCRPC by leveraging tumour-specific adaptive immunity [27]. In the VIABLE phase 3 trial [19], DCVAC/PCa combined with docetaxel and prednisone was well tolerated but failed to improve OS. Treatment-emergent adverse events (TEAEs) were predominantly linked to chemotherapy, with localised injection-site reactions for DCVAC. While prior phase 1/2 studies suggested OS improvements with DCVAC/PCa, the phase 3 results highlight the need for further refinement in vaccine design, including standardisation of preparation, antigen selection, and immune monitoring.

Future vaccine strategies will likely depend on co-stimulatory molecules and cytokines such as GM-CSF [17], which enhance antigen-presenting cell (APC) function and stimulate robust CD4 + and CD8 + T-cell responses. GM-CSF-based approaches have shown promise when combined with tumour vaccines or other immunotherapies [17]. However, challenges persist, including DC heterogeneity, antigen selection, and personalised vaccine development.

The only checkpoint inhibitor ICI evaluated in the RCT in our study was Pembrolizumab, which, when combined with docetaxel and prednisone, demonstrated antitumor activity in chemotherapy-naïve patients previously treated with abiraterone or enzalutamide (KEYNOTE-365) [15]. However, Phase 3 results of KEYNOTE-921 showed no OS improvement when used as maintenance therapy. While adverse events were consistent with the safety profiles of individual agents, most were attributable to the chemotherapy component rather than the immunotherapy [20]. The limited response rates observed may be attributed to rare genetic or molecular defects, underscoring the need for innovative combination strategies to enhance outcomes for prostate cancer patients unresponsive to Pembrolizumab.

Non-randomised studies like CheckMate 9KD, which evaluated nivolumab with docetaxel, demonstrated antitumour activity regardless of prior hormonal therapy, homologous recombination deficiency, or tumour mutational burden [14]. While no new safety concerns emerged, vigilant monitoring for immune-mediated adverse events remains essential. Ongoing trials, such as Phase 3 CheckMate 7DX (NCT04100018) and LORIKEET (phase 2, evaluating lorigerlimab with docetaxel; NCT05848011), may provide further insights into these combinations.

Although no Phase 3 trials of platinum-based chemotherapy with ICIs have been reported, early-phase trials have shown promise. For instance, combining avelumab with carboplatin in heavily pretreated mCRPC patients achieved durable disease control in nearly 70% of cases, with prolonged OS [16]. Interestingly, this efficacy did not correlate with DDR alterations or PD-L1 positivity, suggesting broader applicability. The PAVE-1 trial (NCT03409458) may further support the potential of combining ICIs with chemotherapy or novel agents to enhance therapeutic outcomes.

Improved understanding of the inflammatory pathophysiology of prostate cancer, particularly within the tumour microenvironment (TME), will help refine combinational approaches, such as integrating immunotherapy with chemotherapy [7, 12]. Adverse events remain a critical consideration, with a wide range observed in our study, including fatigue, alopecia, and diarrhoea. Grade 3 adverse events such as neutropenia, febrile neutropenia, and sepsis were predominantly chemotherapy-related.

Additionally, the absence of established predictive markers complicates the selection of mCRPC patients most likely to benefit from immunotherapy with docetaxel. While early findings in other cancers suggested PD-L1 levels as a potential predictor, subsequent studies demonstrated responses in PD-L1-negative tumours, resulting in contradictory evidence [28, 29]. Beyond PD-1/PD-L1, new biomarkers are urgently needed to predict therapy responses. Strategies targeting VISTA-mediated signalling networks, CD73/adenosine pathways, cancer stem cells, and developing chimeric antigen receptor (CAR) T-cell therapies and bispecific antigens could significantly advance treatment [30,31,32].

Expanding beyond classical immune checkpoint inhibition is essential, with a growing emphasis on novel immuno-oncology strategies. For instance, the Phase II trial of XmAb20717 (Vudalimab) explored the use of a bispecific antibody that simultaneously targets PD-1 and CTLA-4, aiming to overcome immunoresistance in patients with mCRPC who had progressed following prior therapy [33]. While final efficacy results are still pending, this approach underscores the potential of dual immune checkpoint blockade to enhance antitumor responses and broaden the effectiveness of immunotherapy in resistant prostate cancer.

Other promising directions include combining immune checkpoint inhibitors (ICIs) with tyrosine kinase inhibitors (TKIs). A recent study evaluating atezolizumab in combination with cabozantinib in mCRPC patients demonstrated encouraging signs of efficacy, despite the historically limited impact of immunotherapy alone in this disease setting [34]. Previously, a randomized, double-blind Phase II trial assessed the efficacy of abituzumab in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy [35]. While overall progression-free survival was not significantly improved compared to placebo, the lower incidence of bone lesion progression in the abituzumab group suggests that biologically targeted antibodies may still play a role in addressing specific clinical outcomes. Although these studies were not included in our meta-analysis due to design differences, they underscore the potential for synergistic effects when ICIs are paired with agents targeting angiogenesis and the tumor microenvironment.

Strengths and limitations

One notable strength of this study is the use of combined hazard ratios (HR) to assess the efficacy, which provides a more comprehensive evaluation compared to median values for overall survival (OS), radiographic progression-free survival (PFS), and time to progression (TTP). The HR accounts for both time and event occurrence [36, 37], enhancing the precision of efficacy outcomes. Additionally, including high-quality studies with low bias risk, such as the KEYNOTE-921 trial, strengthens the reliability of the meta-analysis results, mainly due to the rigorous randomisation processes and objective outcome measures used.

However, this study is not without limitations. There is a limited number of randomised controlled trials (RCTs) on the combination of immunotherapy and docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients, with some studies being phase II or III trials, which may impact the robustness of clinical outcomes.

Although the immunotherapy agents included in our meta-analysis operate through distinct mechanisms of action, they all aim to enhance antitumor immune responses. However, this mechanistic diversity presents a limitation in terms of pooling their outcomes. However, given the scarcity of large-scale RCTs investigating any single immunotherapy strategy in mCRPC, our objective was to evaluate whether the general strategy of combining immune modulation with chemotherapy provides benefit in this patient population. We have therefore presented a pooled estimate while also discussing each agent separately to allow more nuanced interpretation Additionally, the Randomized Phase II Trial [17] included in this analysis presents a high risk of bias, mainly due to its open-label design and incomplete blinding, which may have introduced performance and detection biases. The unclear allocation concealment and incomplete outcome data further raise concerns regarding the study’s internal validity, potentially affecting the pooled effect size and contributing to heterogeneity in the results.

Clinical implications and future recommendations

The combination of immunotherapy and chemotherapy marks a step forward in the treatment of metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT) remains the standard of care, its effectiveness diminishes as the disease progresses to the castration-resistant stage. This underscores the need for novel treatment strategies to extend survival without compromising quality of life. Our findings highlight the importance of precision medicine in the management of mCRPC. Combination therapies are unlikely to provide uniform benefits across the diverse patient population. Thus, biomarker-driven approaches are vital to identify patients most likely to benefit, thereby sparing others from unnecessary toxicity and treatment costs.

A significant challenge of combination therapy is finding the balance between efficacy and safety. Our analysis revealed an increased incidence of immune-related adverse events (irAEs) in combination regimens compared to chemotherapy alone, with conditions such as colitis, pneumonitis, and endocrinopathies potentially impacting patients’ quality of life. These adverse events require prompt recognition and management. Future studies should focus on refining dosing schedules and combinations to minimise toxicity while preserving efficacy.

The high cost of immunotherapy remains an obstacle to its widespread adoption. Although combination regimens may offer survival benefits, the cost-effectiveness of such treatments must be rigorously evaluated, particularly in healthcare systems with limited resources. Collaborative efforts between policymakers, clinicians, and researchers will be necessary to ensure equitable access to these promising therapies.

Conclusion

The combination of immunotherapy and chemotherapy presents considerable potential for addressing mCRPC. Precision and individualised strategies are essential for optimising benefits while minimising adverse effects. Our meta-analysis highlights the need for well-designed, randomised controlled trials (RCTs) to address outstanding questions surrounding optimal combinations, sequencing, and patient selection. The validation of biomarkers, including tumour mutational burden (TMB), microsatellite instability (MSI), and DNA damage response (DDR) mutations, is of paramount importance for their incorporation into clinical practice.

Furthermore, investigating novel combination strategies, including triplet regimens incorporating chemotherapy, immune checkpoint inhibitors (ICIs), and agents targeting the tumour microenvironment (TME) or prostate-specific antigens, could offer enhanced therapeutic options. Evidence derived from varied patient populations in real-world settings will improve the data obtained from randomised controlled trials, offering a more comprehensive insight into these therapies’ long-term safety and efficacy. Incorporating quality-of-life assessments and patient-reported outcomes into clinical trials will be essential for evaluating the broader implications of combination therapies on functional status and symptom burden.

Data availability

Data supporting the findings of this meta-analysis are available from the corresponding author upon reasonable request.

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