Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of androgen deprivation therapy (ADT) to radiotherapy in the RADICALS-HD study did not improve metastasis-free survival compared with no ADT, although it did delay the time to salvage ADT. Furthermore, compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in patients receiving postoperative radiotherapy. This finding was consistent across all prespecified subgroups, including baseline PSA. However, this benefit did not translate into an improvement in overall survival (OS) with a median of 9 years of follow-up.
This metastasis-free survival benefit should be weighed against the extended duration of the well-known adverse effects associated with ADT, such as sexual dysfunction, metabolic syndrome, and osteoporosis. In addition, after 24 months of ADT, testosterone recovery is often prolonged or incomplete, so any adverse effects can be long-lasting according to Prof. Matthew R Sydes of the MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London in London, UK and colleagues who published the findings on 16 May 2024 in The Lancet.
In patients receiving radiotherapy as initial treatment for localised prostate cancer, short-course ADT improves metastasis-free survival and OS, and is a standard of care for those with intermediate-risk and high-risk clinically localised disease. Given the known morbidity of ADT, together with its uncertain long-term benefits, there has been no consensus on the use of short-course ADT in patients receiving postoperative radiotherapy after previous radical prostatectomy.
The RADICALS-HD investigators conducted a large, international, phase III, multicentre, open label, randomised controlled study to address questions of the timing of radiotherapy after surgery and the use of ADT with postoperative radiotherapy across separate randomisations with overlapping patient groups.
The study team tested the efficacy of short-course ADT used in combination with postoperative radiotherapy to the prostate bed. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, PSA less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned 1:1 to radiotherapy only or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, 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 distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The study had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0.67). Analyses followed the intention-to-treat (ITT) principle.
Between 22 November 2007 and 29 June 2015, a total of 1480 patients with a median age of 66 years were randomly assigned to receive radiotherapy only (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9.0 years, metastasis-free survival events were reported for 268 participants, 142 in the radiotherapy only group and 126 in the short-course ADT group (HR 0.886, 95% confidence interval [CI] 0.688–1.140; p = 0.35); 10-year metastasis-free survival was 79.2% (95% CI 75.4–82.5) in the radiotherapy only group and 80.4% (76.6–83.6) in the short-course ADT group.
Toxicity of grade 3 or higher was reported for 121 of 737 patients (17%) in the radiotherapy only group and 100 of 743 patients (14%) in the short-course ADT group (p = 0.15), with no treatment-related deaths.
The authors concluded that the addition of 6 months of ADT to postoperative prostate bed radiotherapy did not improve metastasis-free survival, although it did delay the time to salvage ADT. This reduction in salvage ADT could be considered insufficient to justify 6 months of ADT at the time of radiotherapy. It is unclear whether the reduction in salvage ADT means that some patients will avoid the need for salvage ADT entirely, or whether the start of salvage ADT is merely being delayed. The findings are not sufficient to routinely recommend the use of short-course ADT with postoperative radiotherapy. A meta-analysis of all the randomised trials addressing this issue is warranted.
In a separate article published also on 16 May 2024 in The Lancet, the RADICALS-HD study team reported also on the comparison of short-course versus long-course ADT from this first study to compare different durations of ADT with postoperative radiotherapy after radical prostatectomy in prostate cancer. They wrote that previous evidence supports 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.
In developing the RADICALS-HD study in 2006, the study team hypothesised that long-course ADT would be more effective than short-course ADT in patients receiving postoperative radiotherapy. RADICALS-HD recruited patients due for radiotherapy at any time after previous radical prostatectomy for prostatic adenocarcinoma. Patients 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. The allocated treatment was not masked.
The primary outcome measure was metastasis-free survival. 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% (HR 0.72). Standard time-to-event analyses were used. Analyses followed ITT principle. The RADICALS-HD study originally had disease-specific survival as the primary endpoint, but given accrual rate and power concerns, and ICECaP data showing that metastasis-free survival is a surrogate for OS, the primary endpoint was amended in 2019.
Between 30 January 2008 and 7 July 2015, 1523 patients with a median age 65 years 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, 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 of 753 patients (14%) in the short-course ADT group and for 142 of 757 patients (19%) in the long-course ADT group (p = 0.025), with no treatment-related deaths.
The authors concluded that in this randomised controlled study of patients receiving postoperative radiotherapy after previous radical prostatectomy, long-course ADT for 24 months was more effective than short-course ADT for 6 months in terms of metastasis-free survival, a clinically important long-term outcome measure. This finding was consistent across all prespecified subgroups, including baseline PSA. However, this benefit did not translate into an improvement in OS with a median of 9 years of follow-up. This metastasis-free survival benefit should be weighed against the extended duration of the adverse effects associated with ADT.
In an accompanied comment, Drs. Alan Pollack and Alan Dal Pra of the Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center in Miami, FL, US wrote that radiotherapy only group had a significant risk for additional secondary salvage ADT, which then translates to lifelong ADT intervention, either intermittently or continuously. The administration of secondary salvage ADT before clinical evidence of metastasis would delay metastatic events and has detrimental psychological, economic, and quality-of-life effects that have not been reported in RADICALS-HD. For the short-course ADT versus long-course ADT comparison, the prolongation of ADT to 24 months had an absolute metastasis-free survival benefit of around 6% at 10 years that is counterbalanced by ADT side-effects, including a risk of life-long hypogonadism in nearly half of patients.
When to use long-course ADT is a key question. Although the study investigators did not find distinct pre-radiotherapy PSA subgroups, there is a trend in the reported analyses and a plethora of prospective and retrospective data indicating that higher pre-radiotherapy PSA is associated with increased distant metastasis and reduced OS. The body of data available suggests that long-course ADT or possibly intensified ADT via androgen receptor signalling inhibitors should be considered, particularly when the PSA is greater than 0.5 ng/mL along with consideration of other clinicopathological factors, genomic signatures, and PSA kinetics.
The study was funded by Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
References
- Parker CC, Kynaston H, Cook AD, et al. on behalf of the RADICALS investigators. 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. The Lancet; Published online 16 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00549-X
- Parker CC, Clarke NW, Cook AD, et al. on behalf of the RADICALS investigators. Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial. The Lancet; Published online 16 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00548-8
- Pollack A, Dal Pra A. Androgen deprivation therapy combined with postoperative radiotherapy for prostate cancer management. The Lancet; Published online 16 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00802-X