Effects of enzalutamide, apalutamide, and darolutamide in metastatic hormone-sensitive prostate cancer with or without docetaxel: a systematic review and network meta-analysis

Background: Recently, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been significantly advanced. Androgen deprivation therapy (ADT) was the standard of care for decades. However, as the primary mHSPC treatment, several next-generation androgen receptor inhibitors (NGARIs), such as enzalutamide, apalutamide, and darolutamide are increasingly used. Methods: : A systematic review and network meta-analysis (NMA) was designed to compare the effects of enzalutamide, apalutamide, and darolutamide with or without docetaxel, a taxoid antineoplastic chemotherapy. We searched three databases (Pubmed, Embase, and Cochrane) until March 2022 for patients with mHSPC who were treated with ADT in combination with one of three NGARIs. Docetaxel was administered to few patients. Overall survival (OS) was the primary endpoint. Results: : Survival data were extracted from four trials. It was selected after careful review of 1517 articles. Comparison with ADT monotherapy, combination therapy with enzalutamide, apalutamide, or darolutamide significantly increased OS. Enzalutamide was ranked the first, with an estimated 70.08% probability, followed by apalutamide (66.97%) and darolutamide (62.80%). When administered in combination with docetaxel, darolutamide had the lowest hazard ratio (HR) compared to ADT monotherapy (HR: 0.85, 95% credible interval [CrI]: 0.79–0.91). However, enzalutamide (HR: 0.96, 95% CrI: 0.81–1.1) and apalutamide (HR: 1.1, 95% CrI: 0.75–1.6) did not significantly prolong the OS time. Conclusion: The results of this systematic review and NMA suggest that enzalutamide may be the preferred therapy for mHSPC, followed by apalutamide and darolutamide. Furthermore, NGARIs have been shown to be more effective in patients with mHSPC than ADT. However, only darolutamide may increases OS when combined with docetaxel. Further, there were some potentially critical differences between these trials, such as study design, exist that might affect the outcome. Therefore, when choosing treatment options for different patients with mHSPC, these differences should be considered prior to deciding the best therapy for the patient.