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.
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.
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.
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.
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
In recurrent prostate cancer, the optimal duration of androgen deprivation therapy (ADT) with radiation was not well investigated with only a few randomised controlled trials (RCTs) being performed.
The RADICALS-HD trial recruited patients due for radiotherapy at any point after their previous radical prostatectomy for prostatic adenocarcinoma in an international, phase 3, multicentre, and open-label RCT.
Men were randomly allocated to receive short- versus long- term ADT at 6 months and 24 months, respectively. Minimisation methodology was used with a random element, stratified by the Gleason score (GS), positive margins, radiotherapy timing, planned radiotherapy schedule, and planned ADT type. Men with previous pelvic radiotherapy or previous ADT longer than 8 months or within 6 months before RP were excluded. PSA >5ng/mL, metastasis or other cancers were the other exclusion criteria. The primary outcome measure for RADICALS-HD was metastasis-free survival, which is defined as any distant metastasis or death from any cause. The trial design comprised 80% power with two-sided 5% α to detect an increase in 10-year metastasis-free survival from 75% to 81% (HR 0,72).
Between 2008 and 2015, 1,523 patients were randomised at 138 centres. More than half of men had GS >=4+3, 63% had positive surgical margins and pN+ disease was present in 8%; Early salvage radiation was delivered in 57% and adjuvant radiation in 43%. Lymph nodes were included in the radiation field in 15%.
At a median follow-up of 8.9 years (IQR 7–10), metastasis-free survival was higher in the long-course ADT group (HR 0,773 [95% CI 0,612–0,975]; p=0,029). Time to clinical progression-free survival and time to non-protocol ADT were also slightly improved in the long-course ADT group. However, no benefit on overall survival was noted. Amongst adverse events 13 on 49 in the long- and 5 on 24 in the short-ADT groups were definitely or probably related to ADT. No fatal events related to ADT were recorded.
Overall, 16 patients needed to receive long-course ADT to avoid the development of metastasis within 10 years. This benefit must be weighed against the well-known adverse events related to ADT including sexual and metabolic issues, which may be prolonged as not all men are able to have a full testosterone recovery. The study represents a milestone for ADT duration in the context of salvage radiation. However, several points still need to be considered in clinical practice, and addressed by future trials.
The magnitude of metastasis risk reduction depends on absolute metastatic risk. Those with more aggressive disease features may have improved benefit, and potentially, survival. On the contrary, the risk-benefit ratio of prolonged ADT may not be convenient for those with less aggressive PCa. The DADSPORT (duration of androgen suppression with postoperative radiotherapy) meta-analysis is ongoing and aims to help to define which patients could benefit most from ADT. Further, genomic testing may represent another potentially important tool to optimise risk stratification.
Whilst RADICALS-HD assessed the timing of ADT alone, new generation drugs also require to be tested to verify if they may improve outcomes, especially in those with worse PCa features.
Finally, as patient accrual ended in 2015, PSMA-PET/CT was not performed. The contemporary shift to a “PSMA-PET/CT guided’’ salvage treatment pathway also needs to be kept in mind.