Prostate cancer (PCa) is the second most common malignant tumor worldwide and the fifth leading cause of cancer-related deaths among men (1). Notably, it frequently metastasizes, predominantly to the bones, with approximately 90% of patients with advanced PCa experiencing bone metastases (2). Untreated metastatic PCa typically responds well to androgen deprivation therapy (ADT), also known as metastatic hormone-sensitive prostate cancer (mHSPC) (3). However, most cases eventually progress to metastatic castration-resistant prostate cancer (mCRPC), complicating treatment significantly (4). To address this, novel hormonal therapies (NHTs) have been developed (5–7). Abiraterone was the first NHT used for mCRPC and is recommended as a first-line treatment in numerous studies and guidelines with widely recognized efficacy (8–10). However, abiraterone resistance is a major clinical issue. In addition to abiraterone, enzalutamide (MDV3100) is another first-line NHT for mCRPC (8–10). Some researchers advocate the use of enzalutamide in abiraterone-resistant mCRPC, whereas others opt for docetaxel as a subsequent treatment (11). When both abiraterone and enzalutamide fail, docetaxel chemotherapy is the preferred treatment option. With advances in pharmacology and clinical applications, combinations of various NHTs with docetaxel chemotherapy have been proposed (12, 13). Recent studies have suggested considering a combination of enzalutamide and docetaxel for patients with mCRPC who progress after responding to enzalutamide, although this combined approach is not yet widely used and requires further investigation (13).

Based on this background, we included 67 mCRPC patients who progressed after effective treatment with abiraterone followed by enzalutamide. We investigated the effectiveness of subsequent treatment using enzalutamide combined with docetaxel chemotherapy versus docetaxel alone. This study aims to provide clinical insights for treatment strategies.

The mCRPC stage marks an advanced phase of PCa and significantly reduces patient survival (10). Historically, docetaxel has been regarded as the only drug capable of extending survival in patients with mCRPC (15). It primarily exerts antitumor effects by affecting microtubules, thereby disrupting mitosis and inducing apoptosis (16). However, docetaxel may also benefit patients with prostate cancer through androgen receptor signaling pathways and the inhibition of nuclear translocation (17). Abiraterone is a selective and irreversible CYP17 inhibitor that blocks androgen synthesis from all sources (18). Furthermore, enzalutamide acts by inhibiting the binding, nuclear translocation, and activity of the androgen receptor (19). Both abiraterone and enzalutamide are NHTs that target androgen activity and may lead to cross-resistance, resulting in suboptimal outcomes when switching from abiraterone to enzalutamide (12). However, research indicates that using enzalutamide after abiraterone resistance improves tumor PFS but not overall survival (20). While the mechanism of action of docetaxel shares some similarities with that of enzalutamide, two major studies have demonstrated significant benefits in patients with mCRPC when enzalutamide is used before or after docetaxel (21, 22). Based on these findings and patient preferences, the practice of administering docetaxel chemotherapy following sequential treatment with abiraterone and enzalutamide in patients with mCRPC has become more prevalent than immediately switching to chemotherapy after a single NHT treatment.

The above information suggests that while different drugs have overlapping mechanisms of action, combination therapy may provide better outcomes compared to monotherapy. The PRESIDE study was a two-phase, multinational, double-blind, randomized, placebo-controlled, phase 3b trial conducted at 123 European sites (23). In the first phase, 688 patients with mCRPC received 160 mg enzalutamide daily alongside ADT. After 13 weeks, 271 patients who showed a PSA decline and subsequent progression (radiographic or PSA progression) entered the second phase. All patients underwent 10 cycles of docetaxel chemotherapy (75 mg/m² every 3 weeks) and daily prednisone (10 mg) and were randomly assigned (1:1) to receive either 160 mg/day enzalutamide or a placebo. Results showed that the enzalutamide group had a median tumor PFS of 9.5 months (95% CI: 8.3–10.9 months) compared to the 8.3 months (95% CI: 6.3–8.7 months) in the placebo group (hazard ratio = 0.72, 95% CI: 0.53–0.96, P = 0.027). This indicates that enzalutamide combined with docetaxel could extend tumor PFS in enzalutamide-responsive mCRPC patients beyond that achieved by docetaxel alone. The CHEIRON study involved untreated patients with mCRPC who were randomly assigned (1:1) to receive eight cycles of docetaxel chemotherapy with or without enzalutamide (similar to the PRESIDE protocol) (24). Patients in the combination group exhibited better progression rates after 6 months compared to the docetaxel-only group. These studies highlight the significance of the enzalutamide-docetaxel combination in mCRPC treatment. Unlike the CHEIRON and PRESIDE studies, which did not include patients previously treated with abiraterone, the present study focused on patients with mCRPC who progressed after abiraterone followed by enzalutamide, aligning better with current clinical practices. The study found that even after dual NHT treatment, continuing enzalutamide with docetaxel was more effective than docetaxel alone. The analysis demonstrated that more patients in the combination therapy group experienced >50% PSA decline and improvements in bone and lymph node metastases, highlighting the advantages of combination therapy. Continued follow-up indicated that most patients experienced PSA or imaging progression within one year of treatment. Survival analysis demonstrated more significant benefits for PSA levels and metastasis control with combination therapy, suggesting a synergistic effect between enzalutamide and docetaxel.

Pain is a significant factor that affects the quality of life of patients with advanced malignancies. Both the study and control groups showed a reduction in the VAS scores after treatment, with the study group achieving lower VAS scores, indicating better pain control with combination therapy. This improvement is in line with the greater resolution of bone metastasis and extended PFS in the study group. Clinically, effective medication and care strategies are essential to alleviate pain and enhance patients’ quality of life (25). In terms of adverse reactions, both groups experienced significant myelosuppression, though no Grade III or higher toxicities was observed. Unlike enzalutamide studies, in which myelosuppression was less pronounced, Malinowski et al. (26) indicated that nearly all docetaxel regimens for mCRPC resulted in hematological toxicity, including Grade III-IV neutropenia (12%–15%) and febrile neutropenia (6%–12%). Widespread myelosuppression observed in both groups was likely attributable to docetaxel. Other adverse reactions in the study group included malaise, gastrointestinal responses, lumbago, and backache, consistent with the known side effects of enzalutamide (27). Additional mild adverse effects included liver dysfunction, neurological symptoms, edema, rash, and HBP; however, none necessitated treatment discontinuation. In the control group, aside from myelosuppression, the main adverse reactions were gastrointestinal responses and malaise, with other effects such as liver dysfunction, edema, and neurological symptoms remaining mild (Grades I-II). Overall, although combining enzalutamide with docetaxel introduces enzalutamide-specific adverse effects, these are generally mild and do not require discontinuation or alteration of the treatment regimen, offering an advantage over the use of docetaxel alone.

This study has several limitations that should be acknowledged. First, the follow-up duration was relatively short, which restricted our ability to fully evaluate long-term outcomes such as overall survival (OS). We plan to continue follow-up in future research to address this limitation. Second, as a retrospective study, treatment allocation was determined by physician and patient preference rather than randomization, which may have introduced selection bias and increased the risk of confounding factors affecting treatment outcomes. Third, molecular profiling and biomarker analyses were not performed in this study; however, we intend to conduct further research to evaluate the sensitivity of patients with different genotypes to various treatments. Finally, although pain was assessed using the VAS, other standardized quality of life assessments were not included. In future studies, we will incorporate more comprehensive quality of life measures to provide a deeper understanding of patient-reported outcomes. These limitations underscore the need for prospective, randomized studies with longer follow-up, molecular analyses, and more comprehensive quality of life assessments in future research.

In summary, this study demonstrated that the combination of enzalutamide and docetaxel offers advantages over docetaxel alone in controlling PSA levels and bone metastases in patients with mCRPC who progressed after effective treatment with abiraterone followed by enzalutamide. This combination also helps to alleviate pain symptoms and is associated with relatively mild adverse effects. However, this study was limited by its small sample size and short follow-up period, indicating the need for further analysis and validation with a larger patient cohort.