Background: Early PSA response has been found to be associated with improved outcome in mHSPC patients treated with androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPI). However, it is unknown if the treatment effect on OS varies based on early PSA response in these patients. Methods: We performed a secondary analysis of TITAN study in which men with mHSPC were randomly assigned to ADT plus placebo vs. ADT plus apalutamide (ADT+APA). To compare the association of OS with early PSA response, defined as achieving a PSA nadir of ≤0.2 ng/mL at ≤6 months of randomization, between two arms, we applied multivariable Cox regression model on a landmark population with an interaction term between the treatment arm and PSA response. Adjusted OS were calculated. Confounders were chosen based on their association with PSA response and OS. Results: Overall, 1049 patients were eligible with 526 in the ADT arm and 523 in the ADT+APA arm. Approximately 24% (125/526) patients in the ADT arm and 62% (323/523) patients in the ADT+APA arm achieved early PSA nadir. On landmark analysis, ADT+APA was associated with improved OS among those with an early PSA nadir (HR: 0.66; 95% CI: 0.44-1.00) but no improvement in OS among those without an early PSA nadir (HR: 1.15 [0.87-1.46]) with differential treatment effect between groups stratified by early PSA nadir by 6 months (p=0.03). Adjusted 4-year OS for patients who reached PSA nadir was 66% (95% CI: 56-75) in the ADT alone arm and 78% [74-83] in the ADT+APA arm while for patients who did not reach PSA nadir, adjusted 4-year OS was 46% [41-52] and 47% [40-54] in the ADT alone and ADT+APA arm, respectively. Numbers needed to treat (NNT) was 7.8 (95% CI: 6 to 15) for the overall landmark population, 7.7 [5 to 36] for patients with PSA nadir by 6 months, and 55 [10 to -4] for those without PSA nadir, respectively. Conclusions: In this exploratory analysis of TITAN study, early PSA nadir at or before 6 months was associated with superior OS in both treatment arms. However, there was evidence of differential treatment effect on OS based on early PSA nadir with no beneficial effect from ADT+APA in those who did not reach early PSA nadir. Patients with lack of early PSA nadir had inferior and similar OS in both treatment groups. Further investigation is needed to determine how to best manage patients treated with doublet therapy without an early PSA response.