Background: Little data exist for comparing cardiac safety and survival outcomes of anti-HER2 therapy with concurrent trastuzumab (T) and pertuzumab (P) or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs those in the real world. Furthermore, whether older patients have worse outcomes is unknown. Methods: This was a retrospective population-based cohort of all women with MBC treated with concurrent T with P or TDM1 in Ontario (between 2012 and 2017), identified from New Drug Funding Program and linked to Ontario Cancer Registry and other administrative datasets. Outcomes were incident heart failure (HF, defined as hospitalization or emergency room visit for HF) and overall survival (OS). RCT data were obtained from digitizing survival curves as per established methods and compared with cohort OS data using log-rank test. Age based comparison of outcomes was conducted for women ≥ 65 years old vs younger. Results: Our cohort composed of 833 (28% > 64 years old), and 397 (28% > 64 years old) women treated with P and TDM1, respectively, of which 46 and 30 had baseline HF, respectively. 49% and 99.5% of women received T prior to P and TDM1, respectively. Incident HF following P or TDM1 initiation was low (P 26 women, TDM1 8 women; Table). HF events was not more in women ≥ 65 years old compared to women < 65 treated with P (16 vs. 10, p = 0.23). Unadjusted OS was significantly worse than RCT OS (Table; P HR 1.67, 95% CI 1.37-2.03, p < 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p < 0.0001). Older women had worse OS than younger women for P (HR 1.54, 95% CI 1.22-1.96, p = 0.0003), but not for TDM1 (HR 1.08, 95% CI 0.81-1.43, p = 0.62). Conclusions: HF incidence during P or TDM1 therapy in this real world cohort was relatively low. Survival in this cohort was significantly worse compared to RCT, particularly for older women, suggesting importance of evaluating effectiveness in an unselected patient population to facilitate informed decision-making based on real-world risks and survival outcomes.