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Evaluation of clinical risk stratification to determine benefit from long-term versus short-term androgen deprivation in high-risk localized prostate cancer

Prostate Cancer and Prostatic Diseases (2025)Cite this article

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Abstract

Background

Patients treated with RT and long-term androgen deprivation therapy (ltADT) for high-risk localized prostate cancer (HRLPC) with 1 high-risk factor (any of Gleason ≥8, PSA > 20 ng/mL, ≥cT3; “high-risk”) have better outcomes than those with 2–3 factors and/or cN1 disease (“very high risk”). We evaluated whether this risk stratification could determine benefit from ltADT versus short-term (stADT).

Methods

The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) repository of randomized trials was queried to identify eligible patients and trials. The key outcomes of interest were metastasis-free survival (MFS), overall survival (OS), time to metastasis (TTM) and prostate cancer-specific mortality (PCSM). Stratified Cox and Gray’s regression were used to obtain the overall treatment effect for outcomes and risk groups, and the Wald interaction test to estimate whether treatment benefit differed by risk group or trial. Heterogeneity of studies was assessed by Cochran’s Q and I2.

Results

2780 patients from 3 trials were included. Patients with very-high risk disease had greater benefit with ltADT compared to high-risk disease (MFS HR 0.77 [0.68–0.88] vs. 0.89 [0.76–1.03]; TTM 0.61 [0.51–0.74] vs. 0.77 [0.59–0.99]; PCSM 0.71 [0.56–0.90] vs. 0.82 [0.59–1.14]; OS 0.87 [0.76–1.00] vs. 0.93 [0.79–1.08]), but there was no statistically significant difference in treatment effect by risk group (p-interaction >0.1). Heterogeneity for treatment effect across trials was low in the very high-risk group and moderate in the high-risk group.

Conclusions

Clinical risk stratification merits further evaluation in clinical trials to identify which patients with HRLPC may benefit from ltADT versus stADT.

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Fig. 1: Forest plots showing the treatment comparison of long- vs.

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Funding

Funded by the Prostate Cancer Foundation Challenge Award, and grants from Astellas Pharma, Pfizer, Janssen Pharmaceuticals, Millennium Pharmaceuticals, Sotio, Bayer, Dendreon and Sanofi.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, USA

    Praful Ravi & Wanling Xie

  2. Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland

    Silke Gillessen

  3. Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Bertrand Tombal

  4. University Hospitals Siedman Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Daniel E. Spratt

  5. Brigham & Women’s Hospital, Boston, MA, USA

    Paul L. Nguyen

  6. South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia

    Christopher J. Sweeney

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  1. Praful Ravi
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  2. Wanling Xie
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  6. Paul L. Nguyen
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  7. Christopher J. Sweeney
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Contributions

Conceptualization—PR, WX, CJS; Statistical analysis—WX, Provision of study materials—SG, BT, DES, PLN; Writing (original draft)—PR, WX; Writing (review)—all authors; Funding acquisition—CJS.

Corresponding author

Correspondence to Praful Ravi.

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Competing interests

PR—Research funding to institution from Bayer, Lilly, Telix, Blue Earth Diagnostics, Lantheus, Novartis, Advisory board - Bayer; WX—Consulting Role: Convergent Therapeutics, PCCTC; SG—Personal honoraria for participation in advisory boards from Amgen, MSD; other honoraria from Radio-televisione Svizzera Italiana (RSI), German-speaking European School of Oncology (DESO); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, Speaker’s bureau for Janssen Cilag; travel grant from ProteoMEdiX and AstraZeneca; Institutional honoraria for participation in advisory boards or in Independent Data Monitoring Committees and Steering Committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Bristol-Myers Squibb, DAIICHI Sankyo, Janssen, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma, Tolermo Pharmaceutcials; invited speaker for Swiss group for Clinical Cancer Research (SAKK), Cold Spring Harbor Laboratory, ASCO GU; other honoraria from PeerVoice, Silvio Grasso Consulting, WebMD-Medscape; Patent royalties and other intellectual property for a research method for biomarker WO2009138392; DES—Personal fees: Astellas, AstraZeneca, Bayer, Boston Scientific, GSK, Janssen, Novartis, Pfizer; PLN—research funding paid to institution: Janssen, Astellas, Bayer; Consulting: Boston Scientific, Janssen, Bayer, Novartis, Nanocan; Stock or Other Ownership: Nanocan, Stratagen Bio, Reversal Therapeutics; CJS—research funding paid to institution by Janssen, Astellas, Sanofi, Bayer; Patents, Consulting, or Advisory Role: Sanofi, Janssen, Astellas, Bayer, Genentech/Roche, Pfizer, Lilly; Hengrui; CellCentric, PointBiopharma; Royalties and other Intellectual Property: Parthenolide (Indiana University); dimethylamino parthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination; FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer; Stock or Other Ownership: Leuchemix. All other authors declare to relevant conflicts.

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Ravi, P., Xie, W., Gillessen, S. et al. Evaluation of clinical risk stratification to determine benefit from long-term versus short-term androgen deprivation in high-risk localized prostate cancer. Prostate Cancer Prostatic Dis (2025). https://doi.org/10.1038/s41391-025-00937-0

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  • DOI: https://doi.org/10.1038/s41391-025-00937-0

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