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, MD^1,2; Prof Howard Kynaston, MD³; Adrian D Cook, MSc⁴; Prof Noel W Clarke, ChM^5,6,7; 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, PGCert^1,2,14; Chris Brawley, MSc⁴; Mary Rauchenberger, PhD⁴; Maroie Barkati, MD¹⁵; David M Bottomley, FRCR¹⁶; Klaus Brasso, PhD¹⁷; Hans T Chung, MD^18,19; Peter W M Chung, MBChB^8,19; Ruth Conroy, FRCR²⁰; Alison Falconer, FRCR²¹; Vicky Ford, FRCR²²; Chee L Goh, MD(Res)²³; Catherine M Heath, FRCR²⁴; Prof Nicholas D James, PhD^1,2; 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

Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer

Less radiation is non-inferior, this is for low and intermediate-risk localized prostate cancer patients. Would like input from our radiation oncologists as to whether or not this adoptable?

Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): Phase III Randomized Clinical Trial of Proton Therapy vs. IMRT for Localized Prostate Cancer

Protons vs IMRT for localized prostate cancer showed no difference in outcome or quality of life. There will be longer f/u and other endpoints studied but the take-home message is that protons are not significantly better than photons.

Artificial intelligence and radiologists in prostate cancer detection on MRI (PI-CAI): an international, paired, non-inferiority, confirmatory study

Will we be replaced by AI? It seems that for radiologists, an AI system was better than the human counterpart in this study looking at prostate cancer diagnostic imaging. I doubt many of us would accept a solely computer-generated report, but this study highlights how AI may help as a supportive tool in the primary diagnostic setting. Of course, prospective validation will be needed.

BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm).

We know that combination PARP and antiandrogen is better than antiandrogen alone. I have wondered if we need antiancrogen on those patients. This shows that, YES, we do. The combination also was better than PARP inhibitor monotherapy in those patients carrying HRRm.

Prognostic value of FDG, PSMA, and DOTATATE uptake on PET imaging in metastatic castration-resistant prostate cancer (mCRPC).

It might be costly to get the PET scans but helps with prognosis and directing patients to palliative care since positive lesions in all predicts shorter overall survival.