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

Almudena Zapatero¹Teresa Alonso-Gordoa²Alfredo Rodríguez Antolín³Felipe Couñago^4,5,6Noelia Sanmamed⁷Mario Domínguez Esteban⁸Marta López Valcárcel⁹Ray Manneh¹⁰Ángel Borque-Fernando¹¹Núria Sala-González¹²Pablo Maroto^13*

• ¹Health Research Institute, Hospital Universitario de La Princesa, Madrid, Spain
• ²Ramón y Cajal University Hospital, Madrid, Madrid, Spain
• ³University Hospital October 12, Madrid, Madrid, Spain
• ⁴San Francisco de Asís University Hospital, Madrid, Spain
• ⁵Vithas Madrid La Milagrosa University Hospital, Vithas, Madrid, Asturias, Spain
• ⁶European University of Madrid, Villaviciosa de Odón, Madrid, Spain
• ⁷San Carlos University Clinical Hospital, Madrid, Madrid, Spain
• ⁸Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
• ⁹Puerta de Hierro University Hospital Majadahonda, Madrid, Madrid, Spain
• ¹⁰Society of Oncology and Hematology of Cesar, Valledupar, Cesar, Colombia
• ¹¹Hospital Universitario Miguel Servet, Zaragoza, Aragon, Spain
• ¹²Doctor Josep Trueta Girona University Hospital, Girona, Catalonia, Spain
• ¹³Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

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.