Despite the proven efficacy of androgen deprivation therapy (ADT) combined with androgen receptor pathway inhibitors (ARPIs) in metastatic castration-sensitive prostate cancer (mCSPC), many patients still receive ADT monotherapy due to safety concerns.
This reliance on ADT monotherapy underscores the need for education on the comparative effectiveness and safety of available therapies versus ADT. We evaluated the efficacy and safety of alternative treatment combinations, incorporating final data from the recent ARANOTE Phase III trial.
We conducted network meta-analysis (NMA) to evaluate progression-free survival (PFS) and overall survival (OS), incorporating heterogeneity assessment through subgroup analyses. Additionally, we performed a separate class effect NMA. We analysed grade 3-5 adverse events (AEs), serious AEs, and discontinuation due to AEs. We estimated hazard ratios (HRs) for efficacy, rate ratios (RRs) for safety, 95% credible intervals (CrI), and the surface under the cumulative ranking area (SUCRA) to rank treatments by efficacy and safety.
Darolutamide (DAR) + docetaxel (DOC) + ADT showed the highest effect size [HR of 0.27 (95% CrI: 0.18, 0.39)] and the highest ranking (SUCRA: 0.97) across the base case and several subgroups on the PFS outcome. On OS, DAR + DOC + ADT similarly achieved the lowest HR of 0.52 (0.43, 0.64) and the highest ranking (SUCRA of 0.95). Safety analyses showed that grade 3-5 AEs were more frequent with docetaxel combinations, with ABI + DOC + ADT having the highest risk of grade 3-5 AEs. DAR + ADT was ranked best on all safety outcomes, outperforming other doublets and comparable to ADT monotherapy.
This NMA supports the superior efficacy of ARPI combinations against ADT monotherapy, for both OS and PFS. While DAR + ADT demonstrated comparable efficacy to other doublet combinations, it offered a superior safety profile, making it an effective and safe option for managing patients with mCSPC.
Prostate cancer and prostatic diseases. 2025 Dec 09 [Epub ahead of print]
Neal Shore, Alicia K Morgans, Noman Paracha, Elaine Gallagher, Howard Thom, David Aceituno, Philip Orishaba, Stephen Stefani, Quoc-Dien Trinh, Christopher J D Wallis, Keith R Abrams, Martin Boegemann
Carolina Urologic Research Center, AUC Urology Specialists, Myrtle Beach, SC, USA. ., Dana-Farber Cancer Institute, Boston, MA, USA., Bayer HealthCare Pharmaceuticals, Inc, Basel, Switzerland., Clifton Insight, Bristol, UK., Caixa de Previdência e Assistência dos Servidores da Fundação Nacional de Saúde (CAPESESP), Rio de Janeiro, Brazil., Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada., Department of Statistics & Warwick Medical School, University of Warwick, Coventry, UK., University of Muenster Medical Center, Department of Urology, Muenster, Germany.