An Updated Systematic Review and Network Meta-Analysis of First-Line Triplet Vs. Doublet Therapies for Metastatic Hormone-Sensitive Prostate Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Date 2025 Jan 25

PMID 39857987

Authors

Akihiro Matsukawa

Giulio Litterio

Angelo Cormio

Marcin Miszczyk

Mehdi Kardoust Parizi

Tamas Fazekas

Ichiro Tsuboi

Stefano Mancon

Robert J Schulz

Ekaterina Laukhtina

Pawel Rajwa

Keiichiro Mori

Piotr Chlosta

Michele Marchioni

Luigi Schips

Jun Miki

Takahiro Kimura

Shahrokh F Shariat

Takafumi Yanagisawa

Affiliations

Soon will be listed here.

Abstract

: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. : We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). : A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. : Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

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