De novo patients with high-volume metastatic hormone-sensitive prostate cancer can benefit from the addition of docetaxel to triplet therapy: Network-analysis and systematic review

To the Editor: In recent years, the treatment for metastatic hormone-sensitive prostate cancer (mHSPC) has undergone rapid developments. Docetaxel (DOC) or androgen receptor-targeted agent (ARTA) and androgen deprivation therapy (ADT) are the most commonly used systemic therapies. Multiple meta-analyses or network meta-analyses (NMAs) have been undertaken to evaluate and contrast the various treatment options available for mHSPC. However, the clinical efficacy of DOC in triplet therapy for mHSPC is yet to be confirmed, especially in categorizing the patients based on both volume of disease and timing of metastases. Bringing these controversies to light may have a timely and important impact on further clinical trials. Moreover, based on these trials and our NMA study, triplet therapy has evident benefits on overall survival (OS) and progression-free survival (PFS) in patients with mHSPC. The NMA study presented in this thesis is one of the first studies that assessed the efficacy of DOC and selected patients who will benefit from triplet therapy. Embase, Cochrane Library, and PubMed were systematically searched from inception to July 1, 2024. The OS and PFS were compared via Bayesian NMAs. The current study was registered at PROSPERO (No. CRD42022348505). These meta-analysis and NMA were performed in accordance with the guidelines of The Preferred Reporting Items for Meta-analyses of Observational Studies in Epidemiology Statement [Supplementary Table 1, https://links.lww.com/CM9/C160]. And search strategy is shown in Supplementary Appendix, https://links.lww.com/CM9/C160. The eligible studies examined and compared patients with mHSPC who received triplet therapy, ADT + ARTA, and ADT + DOC (interventions) and those who received other currently available treatment strategies (comparisons) to evaluate the disparate impacts of treatment on OS and PFS. Only randomized clinical trials (RCTs) were considered. Studies without original patient data, reviews, letters, editorial comments, replies from authors, case reports, and articles not written in English were excluded from the analysis. The bibliographic sources of all the included papers were examined for any supplementary research of interest. Flowchart is shown in Supplementary Figure 1, https://links.lww.com/CM9/C160. Two authors independently extracted data. Information on the primary author’s name, publication year, inclusion criteria, agents, agent dosage, number of patients and their age, synchronous disease, disease volume, number of patients treated with DOC, and follow-up periods was collected. Subsequently, the hazard ratios (HRs) and 95% confidence intervals (CIs) from the Cox regression models for OS and PFS were obtained. Any inconsistencies were resolved via consensus with co-authors. The risk of bias assessment of the included RCTs and network plot are shown in Supplementary Figures 2 and 3, https://links.lww.com/CM9/C160. A quality evaluation and assessment of potential prejudice were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions Risk-of-Bias Tool (version 2) (available from www.cochrane-handbook.org). The risk-of-bias diagram was established using the Review Manager 5.3 software (RevMan; The Cochrane Collaboration, Oxford, the UK). The current study utilized forest plots with HRs to examine the correlations between triplet therapy and survival outcomes. OS is defined as the time from treatment initiation to death from any cause. PFS is defined as the time from treatment initiation to disease progression (based on imaging and clinical assessment) or death. Subgroup analyses of patients with high-volume disease (HVD) and low-volume disease (LVD) based on OS and PFS were performed. The CHARRTED trial’s criteria, which include the existence of visceral metastases or four or more bone metastases, with at least one situated outside the pelvic bone or vertebral column, were used to define HVD. A fixed effects model was used to estimate HRs. The heterogeneity among the results of studies incorporated in this meta-analysis was evaluated using the I2-value and Cochrane’s Q test.[1,2] If a notable heterogeneity (P <0.05 in the Cochrane’s Q test) was observed, its root cause was assessed. All calculations were conducted using the R version 4.0.3 software (R Foundation for Statistical Computing, Vienna, Austria), and a P value of <0.05 was considered statistically significant. An NMA utilizing the random-effect models with a frequentist methodology was conducted for direct and indirect treatment comparisons based on OS and PFS. Contrast-based analyses were performed to evaluate OS and PFS, with estimated distinctions in the logarithmic HR and the standard error derived from published HR and CI. The relative effects were presented as HRs and 95% CIs. Subgroup analyses of HVD vs. LVD and synchronous vs. metachronous metastasis with respect to OS and PFS were conducted. In addition, the relative ranking of different treatments for each outcome was evaluated using the SUCRA (surface under the cumulative ranking). Network plots were used to visually represent the interconnectivity of the treatment networks with regard to OS and PFS. All statistical analyses were carried out using R version 4.2.3. According to our inclusion criteria, we finally identified 13 RCTs comprising 13,781 patients eligible for meta-analyses and NMAs [Supplementary Table 2, https://links.lww.com/CM9/C160]. In 13 RCTs, the patients who underwent treatment with DOC + ADT + ARTA in the PEACE-1, ARCHES, ENZAMET, and TITAN trials were derived from their respective subgroup analyses. However, the ARASENS trial was not suitable for PFS analyses due to insufficient data on this endpoint. To prevent data duplication, the comparison of STAMPEDE (arm C and arm G) from the STAMPEDE trial was selected to analyze both OS and PFS in all cohorts. To perform a subgroup analysis of patients with HVD and LVD, the PEACE-1, ENZAMET, GETUG-15, CHARRTED, ARCHES, TITAN, and LATITUDE trials and two studies from the STAMPEDE trial, which examined the differential effects of oncologic outcomes and tumor burden, were selected for NMAs. In particular, the CHART population only included patients with HVD. In addition, survival data for patients with metachronous LVD/HVD are not available. Among patients with high-volume mHSPC, 11 RCTs were included to evaluate OS. As shown in Supplementary Figure 4, https://links.lww.com/CM9/C160, the addition of DOC to ADT + ARTA was associated with a reduced risk of mortality (pooled HR: 0.76, 95% CI: 0.61–0.96). Based on the SUCRA analysis of treatment rankings for OS, the use of triplet therapy was associated with a high likelihood of maximal OS benefit (ADT + ARTA + DOC: 99%, ADT + ARTA: 62%, and ADT + DOC: 38%). There was no significant heterogeneity in all results. In total, nine RCTs were included to evaluate PFS. Supplementary Figure 5, https://links.lww.com/CM9/C160 shows the findings. The addition of DOC to ADT + ARTA was associated with a low hazard of progression (pooled HR: 0.63, 95% CI: 0.42–0.95). In accordance with the SUCRA analysis of treatment rankings for PFS, the use of triplet therapy was associated with a high likelihood of maximal PFS benefit (ADT + ARTA + DOC: 99%, ADT + ARTA: 65%, and ADT + DOC: 35%). There was no significant heterogeneity in all the results. Among patients with low-volume mHSPC, 10 RCTs were included to evaluate OS. As shown in Supplementary Figure 4, https://links.lww.com/CM9/C160, DOC + ADT + ARTA was associated with a reduced risk of mortality (pooled HR: 1.10, 95% CI: 0.72–1.80). Based on the SUCRA analysis of treatment rankings for OS, the use of triplet therapy was associated with a high likelihood of maximal OS benefit (ADT + ARTA + DOC: 73%, ADT + ARTA: 90%, and ADT + DOC: 28%). There was no significant heterogeneity in all results. In total, eight RCTs were included to evaluate PFS. Supplementary Figure 5, https://links.lww.com/CM9/C160 shows the findings. DOC + ADT + ARTA was associated with a low hazard of progression (pooled HR: 1.10, 95% CI: 0.59–2.00). In accordance with the SUCRA analysis of treatment rankings for PFS, the use of triplet therapy was associated with a high likelihood of maximal PFS benefit (ADT + ARTA + DOC: 87%, ADT + ARTA: 79%, and ADT + DOC: 29%). There was not any significant heterogeneity in all the results. Among synchronous patients with high-volume mHSPC, four RCTs were included to evaluate OS. As shown in Figure 1, DOC + ADT + ARTA was associated with a reduced risk of mortality (pooled HR: 0.61, 95% CI: 0.45–0.81). Based on the SUCRA analysis of treatment rankings for OS, the use of triplet therapy was associated with a high likelihood of maximal OS benefit (ADT + ARTA + DOC: 86%, ADT + ARTA: 78%, and ADT + DOC: 33%). There was not any significant heterogeneity in all the results.Figure 1: Forest plot of HR for OS in population of mHSPC patients with synchronous diseases receiving specific therapy compared with the reference group of ADT plus ARTA in this NMA. Forest plot representing HR for combination therapy compared with ADT plus ARTA for HVD (A) and LVD (B). Forest plot representing HR for specific therapy compared with ADT for HVD (C) and LVD (D). SUCRA plot showing the treatment ranking of specific therapies for HVD (E) and LVD (F). Abi: Abiraterone; ADT: Androgen deprivation therapy; ARTA: Androgen receptor-targeted agent; DOC: Docetaxel; Enza: Enzalutamide; HR: Hazard ratio; HVD: High-volume disease; LVD: Low-volume disease; mHSPC: Metastatic hormone-sensitive prostate cancer; NMA: Network meta-analysis; OS: Overall survival; SUCRA: Surface under the cumulative ranking.Among synchronous patients with low-volume mHSPC, four RCTs were included to evaluate OS. As shown in Figure 1, DOC + ADT + ARTA was associated with a reduced risk of mortality (pooled HR: 0.66, 95% CI: 0.42–1.00). Based on the SUCRA analysis of treatment rankings for OS, the use of triplet therapy was associated with a high likelihood of maximal OS benefit (ADT + ARTA + DOC: 77%, ADT + ARTA: 72%, and ADT + DOC: 46%). There was not any significant heterogeneity in all the results. Vale et al[3] revealed that adding DOC to ADT + ARTA is most suitable for mHSPC patients with HVD who had a poor prognosis based on primary tumor volume, which further support the idea of our findings. Previous studies have shown that HVD was found to be associated with a higher frequency of alterations in tumor protein P53 (TP53), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), and retinoblastoma 1 (RB1) than LVD.[4] The alterations of TP53, PI3K3CA, and RB1 can lead to ARTA resistance,[5] which might result in inferior efficiency of doublet therapy in mHSPC patients with HVD compared to triplet therapy. Triplet treatment with DOC can reduce mortality and disease progression compared with ADT + ARTA. Synchronous mHSPC patients with HVD may benefit from DOC in triplet therapy. Doublet therapy without DOC might be the suitable option for people with LVD compared to triplet therapy. Molecular analysis should be conducted to identify the exact mechanisms of therapy resistance. Predictive biomarkers of DOC response are also needed to be explored to allow patients stratification and precision therapy in the future. Acknowledgements We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. Funding This study was funded by grants from the Shanghai Science Committee Foundation (No. 19411967700), the National Natural Science Foundation of China (No. 31570993), and the Wu Jieping Medical Foundation (No. 320.6750.2020-14-7). Conflicts of interest None.