The treatment landscape for advanced prostate cancer has evolved significantly over the past decade. The introduction of docetaxel, androgen receptor pathway inhibitors (ARPIs), poly(ADP-ribose) polymerase inhibitors, and targeted radionuclides has redefined the treatment paradigm, with a focus now on early treatment intensification through combination therapies. This narrative collaborative review summarises the current evidence of combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC).
We conducted a literature search up to November 2024. Search terms included "metastatic hormone-sensitive prostate cancer", "metastatic castration-sensitive prostate cancer", "locally advanced prostate cancer", "combination", "intensification", and "de-escalation". Articles were selected by the authors based on their scientific merit, clinical impact, and relevance to provide a summary of the evidence surrounding combination therapy in locally advanced prostate cancer and mHSPC.
A doublet approach with an androgen deprivation therapy (ADT) backbone and an ARPI is now considered the standard treatment for mHSPC, with a triplet regimen incorporating docetaxel considered in select subgroups. Similar efforts to improve survival in the high-risk localised and locally advanced disease setting have led to several trials evaluating the benefit of combination therapy in addition to standard-of-care surgery or radiotherapy with ADT. Continued improvements in survival have turned the focus to optimising patient selection for treatment intensification and, in some cases, de-escalation, with the goal of reducing unnecessary overtreatment and minimising harm from long-term treatment toxicity. This is particularly important with the integration of prostate-specific membrane antigen positron emission tomography, which has led to the earlier detection of metastatic disease.
In select subgroups, early treatment intensification with combination therapy leads to improved survival, though it can be associated with long-term toxicity.
European urology. 2025 Feb 12 [Epub ahead of print]
Arun A Azad, Louise Kostos, Neeraj Agarwal, Gerhardt Attard, Ian D Davis, Tanya Dorff, Silke Gillessen, Chris Parker, Matthew R Smith, Christopher J Sweeney, Bertrand Tombal, Karim Fizazi
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne Australia. Electronic address: ., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne Australia., Huntsman Cancer Institute, University of Utah Salt Lake City, UT USA., University College London Cancer Institute, London UK., Eastern Health Clinical School, Monash University, Melbourne Australia; Department of Medical Oncology, Eastern Health, Melbourne Australia., Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte CA USA., Oncology Institute of Southern Switzerland, Bellinzona Switzerland; Universita della Svizzera Italiana, Lugano Switzerland; University of Berne, Berne Switzerland; Division of Cancer Sciences, University of Manchester, Manchester UK., Academic Urology Unit, Royal Marsden Hospital, London UK; Institute of Cancer Research, London UK., Massachusetts General Hospital Cancer Center, Boston MA USA., South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide Australia., Cliniques universitaires Saint-Luc, Brussels Belgium., Department of Cancer Medicine, Institut Gustave Roussy, University of Paris-Saclay Villejuif France.