Background: Chemotherapy remains as the only standard treatment option for aTNBC in second and subsequent lines. Entinostat (ENT) is an oral, class I-selective histone deacetylase inhibitor, that has shown antitumor activity in preclinical models of TNBC when combined with immune checkpoint blockade. ENCORE 602 evaluated the efficacy and safety of atezolizumab (ATEZO) + ENT vs ATEZO + placebo (P) in patients (pts.) with pretreated aTNBC. Methods: Pts. with previously treated aTNBC (PD-1/PD-L1 inhibitors naïve) were randomized 1:1 to receive ATEZO (1200 mg IV Q3W) + ENT (5 mg PO QW) or ATEZO+P. Treatment continued until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was PFS as determined by the investigators using RECIST 1.1. The hypothesis was that the combination would improve median PFS by 3 months (hazard ratio = 0.57). Sixty events (from 70 pts.) would provide 80% power with 1-sided significance level of 0.1. Secondary endpoints were PFS per immune-related RECIST (irRECIST), ORR, clinical benefit rate (CBR), Overall Survival (OS), and safety. Results: 81 pts. were enrolled, median age 56 years (range 29-87), 69% received 1 prior line of therapy and 31% > 1 line. No significant difference in PFS per RECIST 1.1 was observed between ATEZO+ENT and ATEZO+P (median PFS 1.68 and 1.51 months, respectively [p = 0.64; HR 0.89, 95% CI: 0.53-1.48]), nor in any of the secondary efficacy endpoints (median PFS per irRECIST 1.68 vs 1.54 months; ORR 10.0% vs 2.4%; CBR 37.5% vs 31.7%; median OS 9.8 vs 12.4 months, respectively). Frequency of treatment-emergent adverse events (TEAEs), SAEs, discontinuations due to TEAE and TEAE with outcome death were higher in the ENT+ATEZO arm. Conclusions: In pts. with previously treated aTNBC, median PFS was not prolonged when ENT was added to ATEZO compared to ATEZO and placebo, and the combination resulted in greater toxicity. Clinical trial information: NCT02708680.