Better Understanding the Timing of Androgen Deprivation (TOAD) Trial Outcomes: Impacts of Prior ADT

Abstract Background The Timing of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate versus delayed androgen deprivation therapy (ADT) for PSA-relapsed or non-curable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen-sensitivity. For these reasons, we completed previously specified sub-group analyses to assess if prior ADT was associated with ADT timing efficacy after PSA-relapse. Methods We examined TOAD trial patient-level data for participants with PSA-relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher’s Exact tests. All hypothesis tests were 2-sided. Results We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs. 9.0 ng/mL, p < 0.01), more cT3 disease (38.4% vs 25.0%, p < 0.01), and more likely received radiotherapy as local treatment (80.0% vs 47.8%, p < 0.01), but were otherwise similar to patients without prior ADT exposure. Within this prior ADT group, those who received immediate ADT (n = 56) had improved overall survival compared to those who received delayed ADT (n = 69, p = 0.02). This benefit was not observed in the group with no prior ADT (p = 0.98). Conclusions The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.