The Efficacy of Cabazitaxel in Treating Prostate Cancer: A Systematic Review and Meta-Analysis

Abstract

Cabazitaxel, a second-generation taxane chemotherapy agent, has demonstrated efficacy in treating metastatic castration-resistant prostate cancer (mCRPC) in patients who have previously received docetaxel-based therapy. By targeting microtubule dynamics, cabazitaxel inhibits cancer cell division and induces apoptosis, thereby extending survival and delaying disease progression in this challenging patient population. A systematic review and meta-analysis were done by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software. Our research reveals significantly improved outcomes in terms of patient survival rates, both progression-free survival (PFS) and overall survival (OS), for cabazitaxel over comparative treatment (PFS HR 0.77 [0.61, 0.97]) (OS HR 0.79 [0.70, 0.88]). The treatment response rates were also favorable for cabazitaxel, reported as PSA Reduction Response of more than 50% (PRR) (odds ratio (OR) = 1.59 [0.56, 4.52]) and tumor response rate (TRR) (OR = 2.34 [1.28, 4.28]). Cabazitaxel was associated with significantly more incidence of adverse events. The risk ratio (RR) for serious adverse events was 1.64 [1.14, 2.35] for cabazitaxel compared to the current regimen. A systematic review and meta-analysis were done by searching in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software.

Introduction

Globally, prostate cancer is one of the most common cancers in males and accounts for a large portion of the yearly death toll from cancer. Prostate cancer is predicted to result in 1.4 million new cases and 375,000 deaths globally in 2020 (Azarenko et al., 2014). Even though there have been advancements in the early detection and treatment of metastatic-resistant prostate cancer (mCRPC), this stage of the disease remains challenging, with limited treatment options. A poor prognosis and the necessity for more potent treatments result from the disease’s development in mCRPC, even in the face of androgen deprivation therapy (Bilusic & Dahut, 2011; Imamura & Sadar, 2016).

The drug’s lower affinity for P-glycoprotein 1 (P-gp), an ATP-dependent drug efflux pump, and its better blood–brain barrier penetration than both docetaxel and paclitaxel served as the basis for its selection for clinical development. Preclinical experiments have demonstrated the potent anticancer activity of cabazitaxel, particularly in cell lines resistant to other taxanes. The enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 are primarily responsible for its metabolism, and within the dose range under investigation, its pharmacokinetics also exhibit linearity (de Wit et al., 2019). Despite these favorable preclinical characteristics, a full evaluation of cabazitaxel’s clinical efficacy and safety profile remains crucial in the context of mCRPC treatment.

Furthermore, the research that is now being published contains inconsistencies and gaps on cabazitaxel, a treatment for metastatic castration-resistant prostate cancer. The technique used in the TROPIC study, which serves as the foundation for the drug’s regulatory approval, needs to be made clear. This highlights how important it is to have a comprehensive synthesis of the evidence to close these gaps (de Bono et al., 2016).

The FDA has approved a number of drugs recently for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including abiraterone, cabazitaxel, and sipuleucel-T. All drugs have shown an improvement in overall survival (OS) of 2 to 4 months in phase III trials relative to comparators (Oudard et al., 2017).

In patients who had progressed after docetaxel treatment, the pivotal TROPIC trial compared the effectiveness of cabazitaxel with mitoxantrone. The results of this trial yielded ground-breaking information about the medication’s use in mCRPC. Cabazitaxel significantly improved OS and PFS when compared to mitoxantrone, even if side effects such as diarrhea and neutropenia were more common with this medication. This highlights the significance of prudent patient selection and management (Annala et al., 2021; Suzuki et al., 2021).

We aim to provide thorough insights into the safety profile, clinical effectiveness, and comparative efficacy of cabazitaxel compared to alternative treatment modalities by synthesizing data from published research. In the end, this research aims to provide guidance for future paths in mCRPC management research as well as clinical practice and health care decision-making.

Method

Data Source and Search Strategy

This systematic review and meta-analysis was conducted in accordance with the International Prospective Register of Systematic Reviews (PROSPERO). The protocol was registered in the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) standards. The objective was to evaluate the efficacy and safety of cabazitaxel in treating prostate cancer.

Using scientific databases such as Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases we conducted the literature from its inception until 01/05/2024. The search strategy was created using the following key terms associated with our study, including “Cabazitaxel,” “prostate cancer,” “treatment,” “efficacy,” “randomized controlled trials,” and “clinical trials.”

Study Selection

Study selection was based on predetermined eligibility criteria. We included randomized controlled trials (RCTs) and non-randomized studies (non-RCTs) that evaluated the efficacy of cabazitaxel in patients with prostate cancer. Studies had to report relevant outcomes such as OS, PFS, and treatment-related adverse events. Exclusion criteria included studies not involving cabazitaxel, studies without sufficient data on efficacy outcomes, reviews, editorials, case reports, and conference abstracts. Only full-text articles published in English were considered (Figure 1).

Figure 1.

Flowchart of the Studies Inclusion Process

Data Extraction and Quality Assessment

The risk of bias in RCTs was evaluated using the Cochrane Risk of Bias (RoB) 2.0 methodology. Identification of the study, participant profiles, intervention specifics, outcome measurements, adverse events, and other pertinent data were all extracted.

Quality assessment was conducted using the Cochrane Risk of Bias (RoB) 2.0 tool, which evaluates the risk of bias across five domains: (a) bias arising from the randomization process, (b) deviations from intended interventions, (c) missing outcome data, (d) measurement of the outcome, and (e) selection of the reported result.

Outcomes of Interest

Outcome measures included changes in OS, PFS, and the incidence of treatment-related adverse events.

Statistical Analysis

Utilizing Review Manager (RevMan) software, statistical analysis was carried out in accordance with Cochrane procedures. Measures like hazard ratios (HRs), odds ratios (ORs), and risk ratios (RRs) with matching 95% confidence intervals (CIs) were used in the research to evaluate outcomes including OS, PFS, treatment response rates, and adverse event incidence.To assess how reliable the results were, subgroup and sensitivity analyses were carried out when necessary.

Results

Five studies published during the period 2010 to 2021 were included in this systematic review with a total of 1,458 participants. The most significant characteristics and outcomes were measured for those patients as the progression-survival rate, OS, response, tumor response, events, and mortality (Table 1). Cabazitaxel achieved an HR of 0.77 (95% CI = [0.61, 0.97]) for PFS and 0.79 (95% CI = [0.70, 0.88]) for OS, indicating important improvements in the survival outcomes. Moreover, at the level of treatment response, cabazitaxel showed a favorable prostate-specific antigen (PSA) reduction response of more than 50% (PRR) with an OR of 1.59, although the CIs suggest variability. The tumor response rate (TRR) also improved significantly, with an OR of 2.34 (95% CI = [1.28, 4.28]), confirming its efficacy in reducing tumor burden. Conversely, the analysis reveals a higher incidence of adverse events associated with cabazitaxel, with an RR of 1.64 (95% CI = [1.14, 2.35]) for serious adverse events, underscoring the treatment’s heightened toxicity profile (Table 1).

Table 1.

The Outcomes and the Data of the Included Studies

		Patients		PFS		Overall survival		PSA reduction response (50% or more)		Tumor response		Safety (serious adverse event)		Mortality
Study		Exp	Control	Exp	Control	Exp	Control	Exp	Control	Exp	Control	Exp	Control	Exp	Control
de Wit et al. (2019) (5)		129	126	8 mo	3.7 mo	13.6 mo	11 mo	35.70%	13.50%	37.00%	#####	38.9	38.7	54.30%	65.90%
de Bono et al. (2010) (6)		378	377	2.8 mo	1.4 mo	15.1 mo	12.7 mo	39.2	17.8	14.4	4.4	39.8	20.75	61%	74%
Oudard et al. (2017) (7)	Cabazi 20 mg/25 mg	389/388	391	4.4/5.1	5.3mo	24.5/25.2mo	24.3mo	60.7/68.7	68.40%	32.4/41.6	#####	34.42/48.08	32.56%	68.8%/63.7	66.90%
Suzuki et al. (2021) (8)		129	126	8.2	3.4	13.9	11.8	37%	14.40%	38.9	11.4	55%	44%	59.8	75.2
Annala et al. (2021) (9)		45	50	5.3	2.8mo	37	15.5	57	54			50%	10%	17	29

The use of cabazitaxel significantly improves survival metrics such as PFS and OS. From the meta-analysis data, cabazitaxel achieves a HR of 0.77 for PFS (95% CI = [0.61, 0.97]; Figure 2) and 0.79 for OS (95% CI = [0.70, 0.88]; Figure 3), which indicates a reduction in the risk of progression or death by approximately 21% to 23% compared to standard treatments. The level of PFS and OS, the respective hazard ratios (HR) of 0.77 (95% CI = [0.61, 0.97]) and 0.79 (95% CI = [0.70, 0.88]), indicated a 23% reduction in the risk of the disease and 21% improvement in overall survival rates compared to standard treatments.

Figure 2.

Progression-Free Survival

Figure 3.

Overall Survival

As cabazitaxel offers significant therapeutic benefits, is associated with a higher incidence of adverse effects, with a RR for serious adverse events of 1.64 (95% CI = [1.14, 2.35]), considering that the adverse events in Annala 2021 were not reported in the control group so outcome cannot be calculated (Figure 4).

Figure 4.

Serious Adverse Events

The RR is 1.46 for prostate-specific antigen (95% CI = [0.75, 2.81]) with a total event of 430 for cabazitaxel and 342 for the standard therapy (Figure 5). TRR RR is 1.94 (95% CI = [1.10, 3.41]; Figure 6).

Figure 5.

Prostate-Specific Antigen

Figure 6.

Tumor Response Rate

Cabazitaxel also confers a survival benefit; the RR for all-cause mortality in the experimental group vs. the control was RR = 0.86 [0.77, 0.96] (Figure 7). Risk of bias was carefully provided including selection, performance, detection, attrition, reporting, and other bias (Figure 8).

Figure 7.

Mortality

Figure 8.

Risk of Bias Summary

Discussion

Interpretation and Contextualization

The effectiveness of cabazitaxel in the reduction of disease progression corroborates the findings from individual studies such as Bono et al. (2010) and de Wit et al. (2019), which have reported benefits of cabazitaxel over standard treatments in specific patient populations. These results reinforce its important and notable role in the therapeutic landscape, particularly with patients who have exhausted other treatment options. The increase in the incidence of the adverse events conducted in our analysis showed an important alignment with the findings from Oudard et al. (2017), and this suggests a careful considerable approach in the clinical practice (Vasani et al., 2011).

Clinical Implications of Cabazitaxel in Prostatic Carcinoma

The use of cabazitaxel significantly improves survival metrics such as PFS and OS. From the meta-analysis data, cabazitaxel achieves a HR of 0.77 for PFS (95% CI = [0.61, 0.97]) and 0.79 for OS (95% CI = [0.70, 0.88]), which indicates a reduction in the risk of progression or death by approximately 21% to 23% compared to standard treatments. This suggests that cabazitaxel emphasizes the potential to extend patient lifespans significantly when other treatments have failed. Furthermore, Carbaxitaxel has shown a marked and important improvement in both PSA reduction and tumor response rates, in which the OR for achieving a PSA response greater than 50% stands at 1.59 (95% CI = [0.56, 4.52]), suggesting a potential increase in biochemical response, although the wide CIs point to some variability in effect size. More strikingly, the TRR with cabazitaxel is reported with an OR of 2.34 (95% CI = [1.28, 4.28]). These findings underscore cabazitaxel’s efficacy is not only delaying disease progression but also reducing tumor burden, which is crucial for symptom management and improving patient quality of life. While cabazitaxel offers significant therapeutic benefits, it is associated with a higher incidence of adverse effects, with a RR for serious adverse events of 1.64 (95% CI = [1.14, 2.35]). The increased risk necessitates a comprehensive approach to patient management, involving preemptive strategies such as dose adjustment, supportive care measures to mitigate side effects, and continuous monitoring for potential complications (de Bono et al., 2010; Hashim, 2020).

Risk-Benefit Assessment of Cabazitaxel in Prostatic Carcinoma

The decision to administer cabazitaxel involves an important and notable evaluation of the balance between its efficacy in improving survival and reducing tumor burden and the potential for significant adverse effects. Our comprehensive analysis meta-analysis incorporated studies by de Bono et al. (2010), Oudard et al. (2017), de Wit et al. (2019), and Annala et al. (2021), in which the findings focused on survival outcomes, treatment response, and adverse events. Where at the level of PFS and OS that are shown in Figures 1 and 2 indicated a 23% reduction in the risk of the disease and 21% improvement in overall survival rates compared to standard treatments. Where according to the metrics, the OR for achieving a PSA reduction greater than 50% is 1.59 (95% CI = [0.56, 4.52]), indicating a favorable biochemical response to cabazitaxel, though the wide CIs suggest variability; moreover, cabazitaxel achieves an OR of 2.34 (95% CI = [1.28, 4.28]), significantly improving tumor reduction. This affirms that cabazitaxel’s capability to not only slow disease progression but also directly decrease tumor size. Furthermore, at the level of safety outcomes, the RR for serious adverse events associated with cabazitaxel is 1.64 (95% CI = [1.14, 2.35]), representing a 64% increase in the likelihood of serious adverse effects, where again, this elevated risk underscores the need for meticulous patient monitoring and proactive management of side effects (Calcagno et al., 2013; Hashim et al., 2024).

Limitations

Our comprehensive analysis of cabazitaxel’s efficacy and safety in treating prostatic carcinoma offers important insights, yet it is essential to consider the limitations in the interpretation and application of the results. The included studies, such as those by de Bono et al. (2010), Oudard et al. (2017), de Wit et al. (2019), and Annala et al. (2021), vary in several aspects including patient demographics, stage of disease, prior treatments, and follow-up durations. Such differences contribute to statistical heterogeneity, which was particularly evident in the forest plots for adverse event outcomes, where I² values indicated substantial variability (I² = 83% for serious adverse events). This heterogeneity suggests that the effects of cabazitaxel might differ across different study settings and populations, potentially affecting the generalizability of the findings. Moreover, some key findings, notably the PSA Reduction Response (PRR) and TRR, exhibited and showed wide CIs (e.g., OR for PRR = 1.59, CI = [0.56, 4.52]), which reflect the uncertainty around these estimates. In addition, the reporting of adverse events varied significantly across studies, impacting the reliability of the aggregated RRs. For serious adverse events, the RR was 1.64 (CI = [1.14, 2.35]), showing a higher risk. However, differences in how side effects were defined, detected, and reported across the trials might influence these findings.

Recommendations for Future Research

Further research should focus on patient subgroups that might benefit the most from cabazitaxel, to enhance both the efficacy and safety outcomes. Exploring combination therapies or adjust treatments that could reduce the adverse effects of cabazitaxel while maintaining or even enhancing its anti-tumor efficacy could also provide significant beneifts.

Conclusion

Prostate cancer represents a significant global issue that leads to a major concern, and it is one of the most common etiology of morbidity and mortality. In 2020, prostate cancer resulted in 1.4 million cases with a high death rate. The second-generation taxane chemotherapy agent, cabazitaxel, is a new FDA-approved drug that has shown promising results in the treatment of prostate cancer. According to the meta-analysis of this study, cabazitaxel is associated with beneficial outcomes including PFS, OS, mortality, response, tumor response, and serious adverse events. Thus, providing the treatment of prostate cancer should be one of the priorities in the medical field.