Background: The use of contemporary androgen receptor signaling inhibitors (ARSI) in combination with docetaxel (Doc) and androgen deprivation therapy (ADT) has shown improved outcomes in recent trials. Prostate specific antigen (PSA) serologic complete response (CR) has correlated with improved overall survival (OS) in prior studies. In the E3805 study, the 12-month PSA CR rate was 28% for the ADT + Doc arm. In this study, we hypothesized the combination of androgen deprivation therapy with Doc and enzalutamide (Enz) would improve the 52-week PSA CR rate compared to the historical control with ADT + Doc in newly diagnosed patients with mCSPC. Methods: The ENZADA trial is a single institution phase II study in patients with mCSPC. Patients received ADT, Doc 75 mg/m2 IV every 3 weeks for up to 6 cycles and Enz 160mg daily until radiographic progression. The primary endpoint was 52-week PSA CR. Secondary endpoints included safety/toxicity, best PSA response, time to castration resistance (TTCR) and overall survival (OS). Patients were stratified by radiographic volume of disease by E3805 criteria. The study was designed with 90% power and 1-sided alpha 0.1 to show an improvement in the 52-week PSA CR from 25% to 45%, with rejection of the null hypothesis if 14 of 39 evaluable subjects achieved a 52-week PSA CR. Results: Between Sep 2017 and Aug 2021, 40 subjects were enrolled, and 36 were evaluable for the primary endpoint. At the data cut-off of 9/2/22, median follow up was 42.6 months. Thirty subjects (75%) had high volume disease, and 32 (80%) subjects presented with de novo metastatic disease. Median age was 64.5 years; 65% (N=26) were identified as White and 35% (N=14) were identified as Black or African American (AA). Median pretreatment PSA was 129.5 ng/ml. 67.5% (27/40) of subjects received six cycles of Doc. 10% (4/40) of subjects had Enz dose modifications. 52-week PSA CR occurred in 22/36 (61.1%) patients (P<0.001). 13/23 (56.5%) White subjects and 9/13 (69.2%) Black or African American subjects experienced 52-week PSA CR (P=.50). Median TTCR was not reached; castrate resistance at 2 and 4 years was 62.4% and 53.5%, respectively. Eleven deaths occurred (3/14 Black or AA and 8/26 White); median OS was not reached. OS at 2 and 4 years was 83.2% and 63.1%, respectively. OS at 2 and 4 years was 85.7% and 78.6%, respectively, in Black or AA subjects and 82.4% and 50.9%, respectively, in White subjects (P=.26). Treatment-related Grade 3-5 adverse events occurred in 17/40 (42.5%) patients, including 3 episodes of febrile neutropenia. Conclusions: ADT+Doc+Enz improved 52-week PSA CR compared to historical control with ADT+Doc. These results are consistent with the recent ARASENS and PEACE1 studies and support the use of triplicate regimens combining ADT+Doc+ARSI in newly diagnosed mCSPC patients. No detectable difference in outcome by race has been observed to date in the study cohort. Clinical trial information: NCT03246347.