Optimal duration of androgen deprivation therapy in combination with post-operative radiotherapy for prostate cancer

The optimal duration of androgen deprivation therapy (ADT) in combination with radiotherapy following radical prostatectomy remains to be subject to debate. The first results of the RADICALS-HD trial now demonstrate that for men with prostate cancer who undergo radical prostatectomy and post-operative radiotherapy, the addition of ADT for 24 months improves outcomes more than administering a short course of ADT (6 months).

Although there is good evidence on the clinical benefit of combining androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for prostate cancer, there is uncertainty on the optimal duration of the ADT in this setting. The RADICALS-HD trial therefore assessed the effect of adding ADT to post-operative radiotherapy on metastasis-free survival (MFS) and compared the efficacy of short vs. long course ADT. Finally, the study investigated the efficacy of ADT in function of comorbidity and PSA levels at time of radiotherapy.

Study design

RADICALS-HD is part of the RADICALS protocol, and consists of a randomised controlled trial assessing the use and duration of ADT with post-operative radiotherapy. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy and no previous post-operative ADT. Prior to post-operative radiotherapy, patients were randomised to either no ADT (“None”), 6 months ADT (“Short”) or 24 months ADT (“Long”). Three-way randomisation was encouraged but two-way randomisation between None vs. Short or Short vs. Long was also allowed. The trial was powered for the two pairwise comparisons. The primary outcome measure was metastasis-free survival (MFS). Secondary outcomes included time to salvage ADT and overall survival (OS). Toxicity assessments focused on radiotherapy with RTOG scale.

Results

From 2007 to 2015, 2,839 patients from the UK, Canada and Denmark joined the RADICALS-HD study, including 492 in the 3-way randomisation. Of them, 1,480 patients contributed to the None vs. Short comparison and 1,523 patients to the Short vs. Long comparison. Arms were balanced within each comparison and risk factors were more favourable in the None vs. Short than in the Short vs. Long comparison.

Median follow-up was 9 years. In the None vs. Short comparison (268 MFS events) the 6 months ADT did not improve the MFS (HR[95%CI]: 0.89[0.69-1.14], p= 0.35; 79% vs. 80% event-free at 10 years). In addition, there was no difference in freedom-from-distant-metastases (FFDM) between both regimens in this comparison. Time to salvage ADT was delayed (HR[95%CI]: 0.54[0.42-0.70], p< 0.0001) but OS was not improved (HR[95%CI]: 0.88[0.65-1.19], p= 0.42). Ten-year OS rates were approximately 85%. In the Short vs. Long comparison (313 MFS events,) 24 months of ADT was shown to improve the MFS (HR[95%CI]: 0.77[0.61-0.97], p= 0.03; 72% vs. 78% event-free at 10 years) over the 6 months option. Also the FFDM was significantly longer for patients receiving 24 months ADT, as compared to those receiving only 6 months ADT (HR[95%CI]: 0.63[0.47-0.85], p= 0.002). Also in this comparison, time to salvage ADT was delayed (HR[95%CI]: 0.73[0.59-0.91], p= 0.005) but OS was not improved (HR[95%CI]: 0.88[0.66-1.17], p= 0.38). With regard to subgroup analysis, there was no significant interaction between the treatment effect and either pre-radiotherapy PSA or comorbidity.

In none of the comparisons a significant difference in RTOG toxicity was observed between the treatment arms.

Conclusion

In receiving having post-operative radiotherapy after radical prostatectomy, 24 months ADT vs.  6 months ADT improved both time to salvage ADT and MFS.  In contrast, 6 months ADT did improve the time to salvage ADT compared to no ADT but did not improve the MFS. These data will allow for a better tailoring of the treatment for prostate cancer patients following surgery and will help to facilitate important discussions.

Reference

Parker C, et al. Duration of androgen deprivation therapy (ADT) with post-operative radiotherapy (RT) for prostate cancer: First results of the RADICALS-HD trial (ISRCTN40814031). Presented at ESMO 2022; Abstract LBA9.