Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine showed clinically meaningful benefits and acceptable tolerability in patients (pts) with HER2+ metastatic breast cancer (MBC) in phase 1 and 2 studies. Methods: This open-label, multicenter, randomized phase 3 study enrolled HER2+ MBC pts after trastuzumab and taxanes, and/or anthracyclines. Up to two prior lines of chemotherapy (chemo) for metastatic disease were allowed. Pts were randomly assigned (1:1) to receive pyrotinib 400 mg or lapatinib 1250 mg qd continuously plus capecitabine 1000 mg/m² bid on days 1–14 of 21-day cycles. The primary endpoint was progression-free survival (PFS) per blinded independent central review. Results: From Jul 2017 to Oct 2018, 267 pts were randomized to the pyrotinib (n=134) or lapatinib (n=133) arm. One pt in the lapatinib arm did not receive study treatment and was excluded from analyses. 42.5% and 34.8% of pts in the pyrotinib and lapatinib arm had no prior chemo for metastatic disease, 41.8% and 49.2% had one prior line, and 15.7% and 15.9% had two lines. At the planned interim analysis, the median PFS was 12.5 months (95% CI 9.7–not reached) with pyrotinib plus capecitabine vs 6.8 months (95% CI 5.4–8.1) with lapatinib plus capecitabine (HR 0.39 [95% CI 0.27–0.56]; P<0.0001), which met the criterion for statistical significance (≤0.0066). Among trastuzumab-resistant pts, prolonged PFS with pyrotinib plus capecitabine was also observed (12.5 months [95% CI 6.9 to not reached] vs 6.9 months [95% CI 5.4 to not reached]; HR 0.60 [95% CI 0.29 to 1.21]). Benefits in objective response rate, clinical benefit rate, and duration of response with pyrotinib plus capecitabine were also indicated (Table). The most common grade ≥3 adverse events were diarrhea (30.6% vs 8.3% in the pyrotinib vs lapatinib arm) and hand-foot syndrome (16.4% vs 15.2%). Conclusions: In pts with HER2+ MBC after trastuzumab and chemo, pyrotinib plus capecitabine achieved a significant better PFS than lapatinib plus capecitabine, with manageable toxicity, verifying the phase 2 findings. Clinical trial information: NCT03080805.