Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial

Abstract

PURPOSE Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS ( P = .10) or OS ( P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

Relative Timing of Radiotherapy and Androgen Deprivation for Prostate Cancer and Implications for Treatment During the COVID-19 Pandemic

“…Discussion | Based on analysis of a large database of patients with unfavorable intermediate-risk, high-risk, or very high-risk PC, later RT initiation up to 6 months after ADT initiation was not associated with worse OS compared with initiating RT before ADT. These results validate the findings of 2 prior randomized trials 2,3 and possibly justify the delay of prostate RT for patients currently receiving ADT until COVID-19 infection rates in the community and hospitals are lower. Limitations of this study included the short follow-up period, retrospective design, lack of information about ADT duration, and possible data entry errors in the database.…”

Moderately hypofractionated radiotherapy for localized prostate cancer: updated long-term outcome and toxicity analysis

“…Interestingly, for the subgroup of high-risk patients in our cohort, the 5‑year bRFS was significantly increased with androgen deprivation therapy (ADT; 5‑year bRFS 90.9% vs. 55.4%, p = 0.008), which clearly underlines the importance of ADT in the high-risk group [ 21 , 22 ], despite treatment with escalated radiotherapy doses. In contrast, the sequence of ADT and radiotherapy appears to be less important [ 23 ]. Short-term androgen deprivation was part of the treatment protocol in the CHHIP trial; it was excluded in the PROFIT trial, which included only patients with intermediate risk.…”

Optimal timing of radiotherapy in high risk prostate cancer: Do missed days matter?

“…Although not tested in high risk disease, the latter has been corroborated with a phase III randomized trial by Malone et al, where there was no statistical difference in biochemical failure free survival between those who initiated ADT at the same time as EBRT or 6 months prior to it. 20 Other independent correlates of improved survival were not particularly surprising, such as younger age, lower comorbidity score, lower PSA, and lower Gleason grade group. Although Asian patients were associated with improved survival, as has been previously demonstrated, 21,22 interestingly there was no such correlation with outcome for white relative to black patients.…”