Comparison of the duration of androgen deprivation therapy in prostate cancer-RADICALS-HD trial

SUMMARY RADICALS-HD (Hormone Duration) was a multinational, open-label, phase three randomized controlled trial performed at 138 accredited centers in Canada, the UK, and Europe between January 2008 and July 2015. This trial recruited patients due for radiotherapy post radical prostatectomy (RP). This trial aimed to compare the efficacy of none vs. short course (6 months) vs. long course (24 months) androgen deprivation therapy (ADT) in the terms of metastasis-free survival (MFS), which was used as a surrogate for overall survival. The secondary outcomes were overall survival, clinical progression-free survival (PFS), and 10-year freedom from distant metastasis and toxicity. The patients with PSA >5 ng/ml, prior pelvic radiotherapy, prior ADT, or metastatic disease were excluded. Among the 2839 RADICALS-HD participants, 1150 patients chose the two way randomization between short course ADT and no ADT. Of the rest of 1689 participants, 1197 chose the two-way randomization (597- short-course ADT and 600 - long-course ADT), and 492 participants chose the three-way randomization (166-no ADT; 164 short course ADT and 162 long course ADT group). Sites were encouraged to randomly allocate patients to a three-way pathway, but they could choose a two-way pathway if the patients were considered unsuitable for the no ADT group. The no ADT group was excluded from the analysis. Finally, a total of 1523 patients with a median age of 65 years were randomly assigned to either receive short course (n = 761) or long course of ADT (n = 762) with a GnRH analog, daily oral bicalutamide, or monthly degarelix. One thousand four hundred and seven (93%) participants had a Gleason score ≥7 and 461 (30%) had stage ≥T3b disease. 63 (8%) participants in the short-ADT and 66 (9%) in the long-ADT arm had pathological nodal involvement (pN+). Four hundred and eighty (63%) participants in the short ADT and 484 (64%) in the long-ADT arm had positive margins. 19% of the participants in the long course ADT arm experienced ≥ grade 3 toxicity compared to 14% in the short ADT arm. The most commonly reported ≥grade 3 toxicities were hematuria and urethral stricture. With a median follow-up of 8.9 years, the notable findings were: The 10-year MFS was 71.9% in the short ADT and 78.1% in the long ADT arm ([HR] =0.77 [95% confidence interval [CI] 0.61–0.97], P = 0.029). Similarly, the 10-year clinical PFS was 66.5% in the short ADT and 73.1% in the long ADT arm. The number needed to treat to avoid one metastasis was 16. The freedom from distant metastasis was superior in the long-course ADT group. However, the benefit did not translate into improvement in the overall survival. Interestingly, when no ADT arm was compared with long-ADT arm, no significant difference was noted in the MFS. To conclude, long-course ADT improved the MFS in patients receiving radiotherapy after RP for prostate cancer by 22% at 9 years. However, the MFS benefit should be weighed against the adverse effects of long-course ADT. COMMENTS RADICALS-HD[1] is a well-conducted, multi-center, randomized trial that compared the efficacy of short-course versus long course ADT in patients requiring adjuvant or salvage radiotherapy following RP. This is the first study in the post-RP settings that contributes level 1 evidence. ADT combined with radiotherapy is recommended by the National Comprehensive Cancer Network for unfavorable intermediate and high risk, localized, and locally advanced prostate cancer based on the RTOG 94-08[2] and 92-02 studies. The concept of adding ADT to the postoperative radiotherapy following RP was established in various phase 3 RCTs, namely RTOG 0534, RTOG 9601, and GETUG-AFU 16. Both RTOG 0534 and 9601 recruited patients with biochemical recurrence following the RP and established the benefit of adding ADT to radiotherapy in terms of OS, MFS, and PFS.[3] In addition, the findings of RTOG 9601[4] pointed out that the benefit in OS with long-term ADT was lower in patients with a lower genomic score. GETUG-AFU 16[5] was another phase 3 RCT which showed benefits in the terms of PFS with short-term ADT and radiotherapy in men with rising PSA following RP. However, no trials have compared the various durations of ADT in the post-RP settings. The limitations of the study include: (i) Data on race and ethnicity were not collected, (ii) The study did not clearly define who would benefit from the long course ADT, (iii) Most patients received radiotherapy to the prostatic bed alone (84%) and it is unclear whether the addition of ADT will benefit the patients receiving pelvic nodal RT as well, (iv) The mortality of carcinoma prostate in this population was 1% at 10 years, so the overall survival benefit is minimal, and (v) This trial was from the pre-PSMA era. The factors that may limit the adoption of long-course ADT in the Indian subcontinent include the adverse effects of testosterone suppression and the cost. Further studies with longer follow-up may help to clarify which subset may benefit from adjuvant hormone therapy/long-course ADT, particularly in the post-prostatectomy settings. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.

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