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Review
. 2025 Jul 25:19:1599292.
doi: 10.3389/or.2025.1599292. eCollection 2025.

Triplet systemic therapy for hormone-sensitive prostate cancer: a critical review with a multidisciplinary approach

Almudena Zapatero  1 , Teresa Alonso-Gordoa  2 , Alfredo Rodríguez Antolín  3 , Felipe Couñago  4   5 , Noelia Sanmamed  6 , Mario Domínguez Esteban  7 , Marta López Valcárcel  8 , Ray Manneh  9 , Ángel Borque-Fernando  10 , Nuria Sala González  11 , Pablo Maroto  12
Affiliations
Review

Triplet systemic therapy for hormone-sensitive prostate cancer: a critical review with a multidisciplinary approach

Almudena Zapatero et al. Oncol Rev. .

Abstract

This article aims to critically evaluate the evidence for triplet therapy consisting of androgen deprivation therapy (ADT), docetaxel and a second-generation androgen receptor pathway inhibitor ([ARPI]; abiraterone, enzalutamide, darolutamide or apalutamide) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), and what this evidence reveals regarding the use of these treatments in clinical practice. A search of PubMed, Medline, Embase, Cochrane, Scopus and Web of Science was conducted in April 2024 to identify relevant prospective and retrospective observational trials, randomized controlled trials (RCTs) and meta-analyses. The search identified 52 relevant articles: six full articles and 31 abstracts based on three RCTs, one observational study and 14 meta-analyses. Abiraterone- or darolutamide-containing triplet therapy was significantly better than ADT + docetaxel for improving overall survival in all study populations, particularly subgroups with high-volume and/or synchronous disease. The tolerability of ADT + docetaxel and triplet therapy were similar with most adverse events related to docetaxel. There were no data comparing triplet therapy with ADT + ARPI doublet therapy. Triplet therapy appears to be the most effective first-line regimen for men with mHSPC, good performance status and high-volume and synchronous metastases. Darolutamide-based triplet therapy may also be of benefit in other patients with high- or low-risk disease. Careful consideration of the risks and benefits are required to determine which patients can be spared from receiving docetaxel and rather be treated with alternative regimens.

Keywords: androgen deprivation therapy; androgen receptor-targeted therapy; docetaxel; hormone-sensitive prostate cancer; metastatic prostate cancer.

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Conflict of interest statement

AZ has received speaker honoraria from Astellas-Pharma; travel expenses from Ipsen, Recordati, and Janssen; and research grants from Janssen. TA-G has received fees for speaker, consultancy, research and other non-financial support from IPSEN, Eli Lilly, Adacap, Pfizer, EISAI, Bayer, Johnson & Johnson, Astellas-Pharma, Roche and MSD. AR has received honoraria for his participation in training and consultancy sessions from Astellas-Pharma, AstraZeneca, Novartis, Bayer and Janssen. FC has received honoraria for participation in expert committees and conferences from Janssen, Astellas, IPSEN, Recordati, Boston Scientific, AstraZeneca and Bayer. NS has served on an advisory board for Astellas-Pharma, and received speaker honoraria from Astellas-Pharma, Janssen, and Bayer, and travel expenses from Ipsen and Recordati. MD has received honoraria for participation in expert committees and conferences from Janssen, Astellas, IPSEN, Bristol Myers Squibb, AAA, Boston Scientific, Intuitive, AstraZeneca and Bayer. ML has received speaker honoraria from Astellas-Pharma, Janssen, and Bayer. RM has served as a speaker, advisory board member and clinical researcher for Astellas, Amgen, Jannsen, Bayer, Pfizer, Novartis, BMS, MSD, Eli Lilly, Roche, Ipsen, Merck Serono and Adium. ÁB-F has participated in training sessions and has received consultancy fees from Asofarma, Astellas-Pharma, AstraZeneca, Bayer, GP Pharm, HealthMDx, Ipsen, Janssen, Lacer, MSD, Pharmalink and Recordati. NS has received research grants, honoraria, and other non-financial support from IPSEN, Pfizer, Bayer, BMS and MSD. PM has received speaker and consultancy fees, and other support such as logistical assistance from Astellas, Janssen, Bayer, MSD and Novartis.

Figures

FIGURE 1
FIGURE 1
Article identification and inclusion.
FIGURE 2
FIGURE 2
Hazard ratio and 95% confidence intervals for overall survival in subgroups of patients in the ARASENS and ENZAMET studies, stratified by metastatic status/volume and/or disease risk (9, 12, 14).
FIGURE 3
FIGURE 3
Hazard ratio and 95% confidence intervals for overall survival in the ARASENS, PEACE-1 and ENZAMET studies, stratified by metastatic volume (12, 13, 14). *95.1% CI.
See this image and copyright information in PMC

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