The optimal sequencing of ADT and radiation has not been clearly defined, but RCT data, meta-analyses, and a systematic review have been published to provide some information on this topic. In the randomized Ottawa 0101 study, neoadjuvant and concurrent ADT for 6 months was compared with concurrent and adjuvant ADT for 6 months.307 No differences were detected in biochemical relapse-free survival or OS. Meanwhile, in NRG/RTOG 9413, a 2 x 2 factorial design was used whereby patients with prostate cancer were randomized to 4 months of neoadjuvant and concurrent ADT (starting 2 months before radiation) versus 4 months of adjuvant ADT, with a second randomization to prostate-only versus whole pelvis irradiation.269, 308 Interestingly, among patients who underwent prostate-only radiation, adjuvant ADT was associated with improved PFS compared to neoadjuvant ADT. However, among patients who received whole pelvis radiation, adjuvant ADT was associated with worse PFS compared to neoadjuvant ADT. In a 2021 meta-analysis by Spratt et al. (including data from Ottawa 0101 and NRG/RTOG 9413), patients receiving neoadjuvant and concurrent ADT and prostate-only radiation were combined into the neoadjuvant group, and patients receiving concurrent and adjuvant ADT were combined into the adjuvant group.309 After a median follow-up of 14.9 years, the adjuvant group had significantly better biochemical control, PFS, and MFS compared to the neoadjuvant group. Of note, patients receiving whole pelvic nodal radiation in NRG/RTOG 9413 were not included in the analysis. There were also systematic differences between the two trials (e.g., duration of ADT, inclusion of more aggressive disease in the NRG/RTOG 9413). As a result, the authors acknowledged that their ability to soundly perform comparative subset analyses was hindered. A 2023 systematic review assessed the question of optimal timing to start ADT in localized prostate cancer.310 A total of 24 studies were included, with 5 studies specifically assessing ADT sequencing with radiotherapy in either the neoadjuvant, concurrent, or adjuvant setting. Included studies were made up of two RCTs, two retrospective studies and one individual patient data meta-analysis. Studies were qualitatively synthesized, and the review found conflicting results. One included study found no difference in any oncological outcomes between adjuvant and neoadjuvant ADT and radiotherapy, while others found that neoadjuvant ADT improved OS, PFS, and biochemical failure. Two included studies, however, found that a concurrent adjuvant sequence of ADT improved biochemical relapse free survival, PFS, biochemical failure, and distant metastasis.310 The authors acknowledged several methodological issues with this systematic review including a limited number of trials comparing neoadjuvant versus concurrent ADT, lack of trials assessing ADT timing in high-risk prostate cancer patients treated with pelvic radiotherapy and ADT, as well as significant heterogeneity of trials in terms of inclusion criteria, risk stratification, and radiation protocols. Despite these methodological shortcomings, the authors supported the use of concurrent ADT for intermediate-risk patients (with neoadjuvant ADT initiation as an acceptable option particularly for patients that may benefit from pre-radiotherapy prostate volume reduction). Short-term neoadjuvant ADT followed by concurrent and long-term adjuvant ADT is recommended (versus concurrent initiation) for high-risk prostate cancer patients. Due to the evolving data in this space, the initiation of adjuvant ADT is no longer recommended.