Addition of Androgen-Receptor Pathway Inhibitors to Standard of Care in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Meta-Analysis - Beyond the Abstract
Our updated systematic review and meta-analysis were not designed to introduce a disruptive new concept, but rather to answer a different and equally important question: how solid is the evidence supporting ARPI plus ADT as a therapeutic class and strategy in mHSPC, in light of the most recent data? By incorporating results from eight randomized phase III trials, including the recently reported ARANOTE study, this analysis provides the most comprehensive and contemporary synthesis of available evidence in this setting. The key message is remarkably consistent. Across more than 8,000 patients, the addition of an ARPI to standard of care significantly reduced the risk of death and progression, with highly homogeneous results across trials, disease burden, timing of metastatic presentation, and treatment strategies. Importantly, this benefit was maintained even when excluding patients who received docetaxel, reinforcing the notion that ARPI plus ADT constitutes a robust and effective backbone therapy in mHSPC.
From an editorial perspective, the relevance of this meta-analysis lies precisely in its lack of surprise. The inclusion of ARANOTE did not alter the direction of effect—it confirmed it. In an era where new data often shift clinical paradigms abruptly, the ability of an updated analysis to reinforce consistency across agents and trials is, in itself, highly informative. These findings support the view that ARPIs behave as a class in this disease setting, with a shared capacity to improve survival when combined with ADT meaningfully.
In my view, this has important implications for daily practice. The question is no longer whether ARPI plus ADT should be offered—it clearly should—but rather what should be added on top of this backbone, and for whom. Looking ahead, the challenge in mHSPC is to validate prognostic and predictive biomarkers to guide treatment selection among available intensification options—whether chemotherapy-based triplets, PARP inhibitor combinations, radioligand therapies, or ARPI-doublets. Disease volume, timing of metastases, and clinical features have served us well as pragmatic tools, but they are increasingly insufficient to capture the biological heterogeneity of mHSPC.
In this context, the strength and consistency of ARPI plus ADT should be viewed as an anchor rather than a ceiling. It provides a reliable therapeutic foundation upon which future biomarker-driven strategies can be built, moving the field from empirical escalation toward precision-guided treatment intensification.
Written by: Brigida Anna Maiorano, MD, PhD, MSc, Genito-urinary Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
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