Background: Treatment goals for pts with metastatic breast cancer include extended survival and improved quality of life (QoL). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received FDA approval for pts with mTNBC who received ≥2 prior chemotherapies (at least 1 in the metastatic setting). In the pivotal phase 3 ASCENT study (NCT02574455), SG demonstrated a significant survival benefit over single-agent chemotherapy TPC in the primary analysis population of pts with second line or greater (2L+) mTNBC without known brain metastases at baseline (Bardia A et al. NEJM 2021) and QoL (Loibl S. et al. ESMO 2021). With additional follow up, we present the final data on efficacy, including overall survival (OS), safety, and QoL. Methods: Pts with mTNBC refractory or relapsing after ≥2 prior chemotherapies with at least 1 in the metastatic setting were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review in pts without known brain metastases at baseline. Key secondary endpoints included OS, safety, and health-related QoL. Safety was analyzed in pts who received ≥1 dose of study drug. Results: Of 529 pts enrolled, 468 did not have known brain metastases at baseline (median age: 54 y [range, 27-82]; median prior lines: 4 [range, 2-17]). As of Feb 25, 2021 (final database lock), SG (n = 235) vs TPC (n = 233) significantly improved median PFS (5.6 vs 1.7 mo; HR: 0.39; P< 0.0001) and median OS (12.1 vs 6.7 mo; HR: 0.48; P< 0.0001). The OS rate at 24 months was 22.4% (95% CI, 16.8-28.5) in the SG arm and 5.2% (95% CI, 2.5-9.4) in the TPC arm. In the safety population (n = 482), key treatment-related grade ≥3 adverse events with SG (n = 258) vs TPC (n = 224) were diarrhea (11% vs 0.4%), neutropenia (52% vs 33%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There was no grade ≥3 neuropathy and 1 case of grade 3 interstitial lung disease reported with SG. No patient experienced a treatment-related death with SG, and there was 1 treatment-related death with TPC due to neutropenic sepsis. Treatment discontinuations due to AEs were ≤3% in both arms. SG arm showed clinically meaningful and statistically significant improvements than the TPC arm in scores for all five primary focus health-related QoL domains. Conclusions: The analysis based on the final database lock of ASCENT confirms the superior survival outcomes of SG over single-agent chemotherapy, with a manageable safety profile and improvement in QoL for pts with mTNBC in the 2L+ setting. These findings reinforce SG as an effective treatment option for this pt population. Clinical trial information: NCT02574455.