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Review
. 2025 Jan 9;17(2):205.
doi: 10.3390/cancers17020205.

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

Akihiro Matsukawa  1   2 , Giulio Litterio  1   3 , Angelo Cormio  1   4 , Marcin Miszczyk  1   5 , Mehdi Kardoust Parizi  1 , Tamás Fazekas  1   6 , Ichiro Tsuboi  1   7 , Stefano Mancon  1   8   9 , Robert J Schulz  1   10 , Ekaterina Laukhtina  1 , Paweł Rajwa  1   11   12 , Keiichiro Mori  1   2 , Piotr Chlosta  1   13 , Michele Marchioni  3 , Luigi Schips  3 , Jun Miki  2 , Takahiro Kimura  2 , Shahrokh F Shariat  1   6   14   15   16   17   18   19 , Takafumi Yanagisawa  1   2
Affiliations
Review

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

Akihiro Matsukawa et al. Cancers (Basel). .

Abstract

Purpose: 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. Methods: 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). Results: 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; p = 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; p = 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; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 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. Conclusions: 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.

Keywords: ARPI; adverse event; docetaxel; mHSPC; network meta-analysis; overall survival; progression-free survival; systematic review; triplet therapy.

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Conflict of interest statement

Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, and Sanofi. Shahrokh F. Shariat received the following: Honoraria: Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Roche, and Takeda Consulting. Advisory Role: Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Pierre Fabre, Roche, and Takeda. Speakers Bureau: Astellas, Astra Zeneca, Bayer, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Richard Wolf, Roche, and Takeda. Pawel Rajwa is a paid consultant/advisor of Janssen. The other authors declare no conflicts of interest associated with this manuscript.

Figures

Figure 1
Figure 1
PRISMA 2020 flow diagram.
Figure 2
Figure 2
Network meta-analyses, (A) PFS, (B) OS, and (C) AEs. Abbreviations: Abi = abiraterone; ADT = androgen deprivation therapy; AE = adverse event; Apa = apalutamide; ARPI = androgen receptor pathway inhibitor; CI = confidence interval; Dar = darolutamide; Doc = docetaxel; Enz = enzalutamide; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; RR = risk ratio.
Figure 2
Figure 2
Network meta-analyses, (A) PFS, (B) OS, and (C) AEs. Abbreviations: Abi = abiraterone; ADT = androgen deprivation therapy; AE = adverse event; Apa = apalutamide; ARPI = androgen receptor pathway inhibitor; CI = confidence interval; Dar = darolutamide; Doc = docetaxel; Enz = enzalutamide; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; RR = risk ratio.
Figure 3
Figure 3
Forest plot of network meta-analyses of individual regimens, (A) PFS and (B) OS. Abbreviations: Abi = abiraterone; ADT = androgen deprivation therapy; Apa = apalutamide; Dar = darolutamide; Doc = docetaxel; Enz = enzalutamide; OS = overall survival; PFS = progression-free survival.
See this image and copyright information in PMC

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