Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Author(s): Prof Chris C Parker, MD1,2; Prof Howard Kynaston, MD3; Adrian D Cook, MSc4; Prof Noel W Clarke, ChM5,6,7; Prof Charles N Catton, FRCPC8; William R Cross, PhD9; Peter M Petersen, PhD10; Prof Rajendra A Persad, FRCS(Urol)11; Cheryl A Pugh, BSc4; Prof Fred Saad, MD12; John Logue, FRCR5; Prof Heather Payne, FRCR13; Lorna C Bower, PGCert1,2,14; Chris Brawley, MSc4; Mary Rauchenberger, PhD4; Maroie Barkati, MD15; David M Bottomley, FRCR16; Klaus Brasso, PhD17; Hans T Chung, MD18,19; Peter W M Chung, MBChB8,19; Ruth Conroy, FRCR20; Alison Falconer, FRCR21; Vicky Ford, FRCR22; Chee L Goh, MD(Res)23; Catherine M Heath, FRCR24; Prof Nicholas D James, PhD1,2; Charmaine Kim-Sing, FRCPC25; Ravi Kodavatiganti, MD26; Prof Shawn C Malone, FRCPC27; Stephen L Morris, FRCR14; Prof Abdenour Nabid, FRCPC28; Aldrich D Ong, FRCPC29; Rakesh Raman, FRCR30; Sree Rodda, FRCR31; Paula Wells, PhD32; Jane Worlding, FRCR33; Prof Wendy R Parulekar, MD34; Prof Mahesh K B Parmar, DPhil4; Prof Matthew R Sydes, MSc4
Source: DOI:https://doi.org/10.1016/S0140-6736(24)00549-X

Dr. Maen Hussein's Thoughts

10-year metastasis-free survival was 71.9% in the short-course ADT group (6 months) and 78% in the long-course ADT group (24 months). So, it seems the longer the duration, the better the outcome. 93% had a Gleason score of 7 or higher.

BACKGROUND

Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.

METHODS

RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.

FINDINGS

Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.

INTERPRETATION

Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.

FUNDING

Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Author Affiliations

1The Royal Marsden NHS Foundation Trust, London, UK; 2The Institute of Cancer Research, London, UK; 3Division of Cancer and Genetics, Cardiff University Medical School, Cardiff, UK; 4MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK; 5Department of Urology, The Christie NHS Foundation Trust, Manchester, UK; 6Division of Cancer Sciences, University of Manchester, Manchester, UK; 7Department of Urology, Salford Royal Hospital, Salford, UK; 8Princess Margaret Cancer Centre, Toronto, ON, Canada; 9Department of Urology, St James’s University Hospital, Leeds, UK; 10Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 11Department of Urology, Bristol Urological Institute, Bristol, UK; 12Department of Urology, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; 13The Prostate Centre, London, UK; 14Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 15Department of Radiation Oncology, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; 16Department of Clinical Oncology, St James’s University Hospital, Leeds, UK; 17Department of Urology, Copenhagen Prostate Cancer Center, Rigshospitalet, Copenhagen, Denmark; 18Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; 19Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; 20Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; 21Radiotherapy Department, Charing Cross Hospital, London, UK; 22Royal Devon and Exeter University NHS Foundation Trust, Exeter, UK; 23Royal Surrey County Hospital, Guildford, UK; 24Department of Clinical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 25Department of Radiation Oncology, BC Cancer—Vancouver, Vancouver, BC, Canada; 26Glan Clwyd Hospital, Betsi Cadwaladr University Health Board, Bangor, UK; 27The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; 28Service de Radio-Oncologie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; 29Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 30Kent Oncology Centre, Kent and Canterbury Hospital, Canterbury, UK; 31Bradford Teaching Hospitals, Bradford, UK; 32Barts Cancer Centre, St Bartholomew’s Hospital, London, UK; 33University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; 34Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada

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