Background: P provides a progression-free and overall survival (PFS, OS) benefit in HER2-positive MBC, and is standard of care in the 1^st line. Continuing H post-progression on 1^st-line H improves response and time to progression. H + X is well tolerated and more effective than X in these pts, and dual P + H anti-HER2 therapy has activity in this population. However, efficacy and safety of P + H + X is unknown. We report the primary analysis of a multicenter, open-label randomized study of H + X vs P + H + X (NCT01026142). Methods: Pts who received a prior taxane and progressed during/after 1^st-line H-based therapy for HER2-positive MBC were randomized to intravenous (IV) H 8 mg/kg then 6 mg/kg q3w + oral X 1250 mg/m² twice daily (2 weeks on, 1 week off q3w; Arm A) or IV P 840 mg then 420 mg q3w + IV H per Arm A + oral X per Arm A but at 1000 mg/m² (Arm B). The primary endpoint was independent review facility-assessed PFS (IRF PFS). The secondary endpoints of OS and safety are also reported. Hierarchical testing procedures were used to control type I error in the multiple statistical testing of IRF PFS and OS. Results: At clinical cutoff (5/29/15), 224 pts had been randomized to H + X and 228 to P + H + X (ITT populations; median follow-up 28.6 and 25.3 months, respectively). Baseline demographics/characteristics were generally balanced across arms. Median IRF PFS was 9.0 months in Arm A vs 11.1 months in Arm B (HR 0.82, 95% CI 0.65‒1.02; p = .0735). Interim OS was 28.1 months in Arm A vs 36.1 months in Arm B (HR 0.68, 95% CI 0.51‒0.90). Adverse events (AEs) were reported in 214/218 pts (98.2%) in Arm A vs 222/228 (97.4%) in Arm B; grade ≥ 3 AEs in 130 (59.6%) vs 118 (51.8%), and treatment discontinuations due to AEs in 42 (19.3%) vs 48 (21.1%), respectively (safety populations). Conclusions: PHEREXA did not meet its primary endpoint of IRF PFS. An 8-month improvement in median OS with P to 36.1 months was observed. Statistical significance for OS cannot be claimed due to the hierarchical testing; however, the magnitude of benefit is in keeping with prior experience of P in MBC. No new safety signals were identified. Clinical trial information: NCT01026142