Sequencing of Androgen Deprivation Therapy of Short Duration with Radiotherapy for Non-Metastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

Abstract

<h3>Purpose/Objective(s)</h3> Prior evidence from randomized controlled trials (RCTs) suggests that sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) impacts clinical outcomes, with a potential interplay with pelvic nodal RT (PNRT). Herein, we aim to further investigate this finding across 12 RCTs, and assess the interplay of ADT sequencing with PNRT in localized prostate cancer (LPCa). <h3>Materials/Methods</h3> The Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) consortium was accessed to obtain individual patient data (IPD) from 12 RCTs that included patients with LPCa who received neoadjuvant/concurrent (neo/conc) or concurrent/adjuvant (conc/adj) short-course ADT (4-6 months) with either prostate-only RT (PORT) or PNRT. Inverse probability of treatment weighting (IPTW) analyses were performed to balance treatment groups, with weights derived from propensity scores as a function of age, initial PSA, Gleason Score, T stage and mid-trial enrollment year. The primary endpoint was metastasis-free survival (MFS), as assessed by IPTW-adjusted Cox regression. IPTW-adjusted Fine and Gray competing risk models were developed to evaluate biochemical recurrence (BCR), distant metastasis (DM) and prostate cancer-specific mortality (PCSM). The regression models include ADT sequencing, PNRT and their interaction to account for effect modification. <h3>Results</h3> Overall, 7409 patients were included (6325 neo/conc, 1084 conc/adj) with a median follow-up of 10.2 years (10.3 neo/conc, 9.9 conc/adj). Conc/adj ADT was associated with improved MFS (10-year estimates: 66.3% vs. 60.6%, HR 0.70 [95% CI 0.59-0.83], p<0.0001), BCR (26.2% vs. 35.2%, sHR 0.43 [95% CI 0.34-0.56], p<0.0001), DM (11.5% vs. 9.0%, sHR 0.55 [95% CI 0.36-0.85], p=0.0073), and PCSM (4.6% vs. 6.2%, sHR 0.33 [95% CI 0.19-0.57], p<0.0001). A significant interaction between ADT sequencing and PNRT for all the above endpoints was observed (P-interaction <0.0001 for all). In patients receiving PORT, conc/adj ADT was associated with significantly improved BCR, DM, MFS and PCSM. In contrast, patients receiving PNRT neoadj/conc ADT was associated with significantly improved DM, MFS and PCSM. Comparing the 4 groups based on ADT sequencing and use of PNRT, after IPTW, conc/adj ADT with PORT (reference) had superior MFS compared to neo/conc + PORT (HR 1.59 [95% CI 1.33-1.91], p<0.0001), neo/conc + PNRT (HR 1.96 [95% CI 1.60-2.39], p<0.0001), or conc/adj +PNRT (HR 1.94 [95% CI 1.51-2.50], p<0.0001). <h3>Conclusion</h3> The sequencing of ADT with RT was significantly associated with clinical outcomes, with evidence of a significant interaction based on use of PNRT. PORT with conc/adj vs. neo/conc ADT had improved MFS, while PNRT with neo/conc vs. conc/adj ADT had improved MFS. Overall PORT with conc/adj ADT had superior outcomes. Given the non-randomized nature of the current pooled analysis, we await the results of NRG/RTOG 0924 to understand the role of PNRT in LPCa with neo/conc ADT sequencing.