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

Abstract

Background

Our prior STOPCAP systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer (mHNPC) 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 performed based on aggregate data (AD) from all available studies.

Methods

Overall survival (OS) and failure-free survival (FFS) data from completed STOPCAP reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was overall survival (OS). Correlations between treatment comparisons within one multi-arm multi-stage (MAMS) trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.

Results

We 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 (HR = 0.61, 95% 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) and 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 FFS (100% probability). Doc was the second-best treatment for overall survival (35% probability).

Conclusions

Uniquely, we have included all available results and appropriately accounted for inclusion of MAMS trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with mHNPC. 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.