Our prior STOPCaP systematic reviews showed improved survival for men with metastatic hormone-sensitive prostate cancer (mHSPC) 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.
Overall survival (OS) data from completed reviews of DOC, ZA and AAP and from recent trials of ZA and CEL contribute to this new comprehensive AD-NMA. Correlations between treatment comparisons within multi-arm multi-stage (MAMS) trials (e.g. STAMPEDE) were estimated from control-arm event counts in overlapping recruitment periods. We assumed network consistency and a common heterogeneity variance.
Network estimates of effects on OS were consistent with reported comparisons with ADT alone for: AAP (HR = 0.61, 95% CI 0.51-0.76); DOC (HR = 0.74, 95% CI 0.65-0.85); CEL+ZA (HR = 0.77 95%CI 0.62-0.96) and DOC+ZA (HR = 0.78 95% CI 0.65-0.93). The effect of CEL+ZA is consistent with the additive effects of the individual treatments. Based on the current data, the network OS results suggest that AAP has the highest probability of being best, and DOC second-best. ADT, ZA and CEL have the highest probability of being worst. Results for failure-free survival will be presented.
Uniquely, we have included all available results and appropriately accounted for inclusion of MAMS trials in this AD-NMA. Our results clearly support the use of AAP or DOC with ADT in men with mHSPC; direct evidence from the STAMPEDE trial (Abstract #3632) and the ongoing PEACE-1 trial (NCT01957436) will corroborate (or otherwise) their relative effects. A NMA based on individual participant data is in development to fully account for patient variability across trials, changes in prognosis or treatment effects over time, and the potential impact of treatment on progression.
Clinical trial identification
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University College London
UK Medical Research Council
J. Carpenter: Funded by the MRC, HEFCE and contributions from NIHR, ESRC, MRC and EU funds. He undertakes methodological consultancy work for Novartis and GlaxoSmithKline, and has given courses for GlaxoSmithKline, Bayer and Boehringer. N.W. Clarke: Advisory Boards: Astellas, Janssen, Ferring, Bayer, AstraZeneca; Corporate-sponsored Research: AstraZeneca. K. Fizazi: Advisory boards for Sanofi and Novartis. G. Gravis: Travel grants from Sanofi, Astellas and Janssen. N.D. James: Grants, personal fees and non-financial support from Janssen, Astellas, Sanofi, Novartis during the conduct of the study; grants and non-financial support from Clovis Oncology, Pfizer M.D. Mason: Delivering a paid lecture for Janssen and has been an advisory board member for Sanofi and Bayer. M.K. Parmar: Grants from Astellas, Janssen, Novartis, Pfizer, Sanofi and Clovis Oncology C.J. Sweeney: Ownership BIND; Advisory board Astellas/Medivation, Astra Zeneca, Sanofi, Janssen, BIND, Bayer; Grants Janssen, Astellas/Medivation, Sanofi, Janssen, Soti, Exelixis; Consultancy Astellas/Medivation, Pfizer, Sanofi, Janssen, BIND, Bayer, Genentech. M.R. Spears, M.R. Sydes: Grants from Astellas, Janssen, Novartis, Pfizer, Sanofi and Clovis Oncology. All other authors have declared no conflicts of interest.