What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis

Abstract

BackgroundOur prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies.MethodsOverall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.ResultsWe identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53–0.71], Doc (HR = 0.77, 95% CI 0.68–0.87), ZA + Cel (HR = 0.78, 95% CI 0.62–0.97), ZA + Doc (HR = 0.79, 95% CI 0.66–0.94), Cel (HR = 0.94 95% CI 0.75–1.17) and ZA (HR = 0.90 95% CI 0.79–1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability).ConclusionsUniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Adaptive platform trials using multi-arm, multi-stage protocols: getting fast answers in pandemic settings

“…This collaboration could be achieved using the prospective framework for adaptive meta-analysis (FAME), which has been successfully used to pool data across ongoing trials of prostate cancer 33 , and helped facilitate the identification of patient subgroups for whom individual treatments may be most effective 34 . In the COVID 19 setting, meta-analysis using individual participant data (IPD) may be key to delineating which treatment strategies are most effective in individual patients 35 .…”

Novel treatment options in the management of metastatic castration-naïve prostate cancer; which treatment modality to choose?

“…Additionally, several meta-analyses have made some cautious, indirect comparisons on the best treatment of mCNPC patients in terms of OS and other end points [25][26][27][28][29][30][31][32]. A 23-27% reduction in the risk of death was observed when ADT was combined with docetaxel compared with ADT alone with pooled HRs of 0.73-0.77, and the addition of abiraterone to ADT resulted in a 37%-40% reduction in risk of death with pooled HRs of 0.60-0.63 (Table 4).…”

Evidence Synthesis to Accelerate and Improve the Evaluation of Therapies for Metastatic Hormone-sensitive Prostate Cancer

“…In this scenario, network meta-analysis can be used to make optimal use of both the direct and indirect comparisons of treatments from all trials, and to allow the relative effects of all treatments to be ranked (19,20). For example, a network meta-analysis that included the FAME reviews described above plus a trial of of celecoxib, generated a thorough overview of the effects of all current treatments (Figure 2), and provided substantial evidence that overall, abiraterone is the most effective treatment for mHSPC to date (21). However, this is in contrast to the results of a direct comparison of these agents based on a small subset of patients from the STAMPEDE trial (22).…”