Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis

Purpose: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available docetaxel-based systemic triplet therapies for metastatic hormone-sensitive prostate cancer (mHSPC). Methods: We searched for eligible publications in PubMed, Embase, and Cochrane CENTRAL. Improvements in overall survival (OS) and radiographic progression-free time (rPFS) were compared indirectly using network meta-analysis and evaluated using the surface under the cumulative ranking curve (SUCRA). Other secondary endpoints, such as time to castration-resistant prostate cancer and/or adverse events (AEs), were also compared and evaluated. Results: Five trials were selected and analyzed using a network meta-analysis. Compared to androgen deprivation therapy (ADT) plus docetaxel, darolutamide (hazard ratio [HR]: 0.68, 95% credible interval [CrI]: 0.57–0.80) and abiraterone (HR: 0.75, 95% CrI: 0.59–0.95) triplet therapy had significantly longer OS, and darolutamide triplet therapy was the first treatment ranked. Abiraterone (HR: 0.49, 95% CrI: 0.39–0.61) and enzalutamide (HR: 0.52, 95% CrI: 0.30–0.89) had significantly better rPFS than ADT plus docetaxel; however, all three therapies, including abiraterone, apalutamide, and enzalutamide, were the best options with a similar SUCRA. At most secondary endpoints, systemic triplet therapy was superior to ADT plus docetaxel. The risk of any AEs in darolutamide or abiraterone triplet therapy was comparable with ADT plus docetaxel (odds ratio [OR]: 2.53, 95% credible interval [CrI]: 0.68–12.63; OR: 1.07, 95% CrI: 0.03–36.25). Abiraterone triplet therapy had an increased risk of grade≥3 AEs (OR: 1.56, 95% CrI: 1.15–2.11). Conclusion: Systemic triplet therapy was more effective than ADT plus docetaxel for mHSPC. Of the triplet therapy regimens, darolutamide ranked first in terms of improved OS. Abiraterone and enzalutamide triplet ranked first in terms of rFPS, however, it did not confer a statistically difference among all triplet regimens. The overall risk of AEs was comparable. More studies are required for current and potential combinations of systemic triplet therapy.


Rationale
3 Describe the rationale for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted.

Supplementary Table1
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the metaanalysis). Page2-3,line211-219 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Page3,line224-235

Data items 11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Geometry of the network S1 Describe methods used to explore the geometry of the treatment network under study and potential biases related to it. This should include how the evidence base has been graphically summarized for presentation, and what characteristics were compiled and used to describe the evidence base to readers.

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Risk of bias within individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

S2
Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied. Describe efforts taken to address its presence when found.
Page4,line371,line407-Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Supplementary Figure 1
Additional analyses 16 Describe methods of additional analyses if done, indicating which were pre-specified. This may include, but not be limited to, the following:  Sensitivity or subgroup analyses;  Meta-regression analyses;  Alternative formulations of the treatment network; and  Use of alternative prior distributions for Bayesian analyses (if applicable).

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Figure 1
Presentation of network structure

S3
Provide a network graph of the included studies to enable visualization of the geometry of the treatment network.

Figure 2
Summary of network geometry

S4
Provide a brief overview of characteristics of the treatment network. This may include commentary on the abundance of trials and randomized patients for the different interventions and pairwise comparisons in the network, gaps of evidence in the treatment network, and potential biases reflected by the network structure.

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Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Page3,line296-300； Table 1 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment.
Supplementary For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group, and 2) effect estimates and confidence intervals. Modified approaches may be needed to deal with information from larger networks.  presented.

Exploration for inconsistency S5
Describe results from investigations of inconsistency. This may include such information as measures of model fit to compare consistency and inconsistency models, P values from statistical tests, or summary of inconsistency estimates from different parts of the treatment network. Page4,line371,line407-408 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies for the evidence base being studied.
Supplementary Table 5 Results of additional analyses 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression analyses, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth).

Summary of evidence 24
Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy-makers).
Supplementary Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. This should also include information regarding whether funding has been received from manufacturers of treatments in the network and/or whether some of the authors are content experts with professional conflicts of interest that could affect use of treatments in the network. PICOS = population, intervention, comparators, outcomes, study design. * Text in italics indicateS wording specific to reporting of network meta-analyses that has been added to guidance from the PRISMA statement. † Authors may wish to plan for use of appendices to present all relevant information in full detail for items in this section.