Background: P is an orally active inhibitor of CDK4/6. In a randomized phase II study, P + L significantly prolonged progression-free survival (PFS) vs L alone (20 vs 10 mo; HR = 0.488, P =0.0004; Finn et al, Lancet Oncol, 2015) in ER+/HER2- ABC as first-line treatment. Given that pts who did not receive any systemic treatment (ST) may have different disease biology/course from those treated and relapsed from early stage disease and many pts may initiate endocrine therapy (ET) alone, we investigated the benefit of P + L in this subgroup in the PALOMA-1/TRIO-18 study. Methods: 165 ER+ and HER2- postmenopausal pts who are treatment naïve for their ABC were randomized to receive L (N = 81) or P+L (N = 84). A subset of pts did not receive any ST in the adjuvant setting prior to randomization (P+L n = 44, L n = 37). The primary endpoint was investigator-assessed PFS. Tumor assessment was performed every 8 weeks. Tumor tissues were collected for correlative biomarkers. Results: Clinical characteristics at baseline were well balanced on median age (P+L vs. L: 63 vs 62), ECOG PS (0/1 59%/41% vs. 49%/51%) and site of disease (visceral/bone only/other: 55%/14%/32% vs. 51%/14%/35%). Observed mPFS was 24 m (95% CI 13, 35) for P+ L vs. 8 m for L (95% CI 6, 13) with HR = 0.315 (95% CI 0.175-0.566) (p < 0.0001). Overall response rate (ORR) was 48% (95% CI 33%, 63%) vs. 41% (25%, 58%); clinical benefit rate (PR+SD ≥ 24 wks) was 84% (70%, 93%) vs. 70% (53%, 84%). The most common treatment emerged adverse events (all grades) for P + L arm were neutropenia (67%), fatigue (49%), leucopenia (49%), and anemia (35%), consistent with the overall safety profile. Tissue samples were available in 73 pts. Loss of RB expression by immunohistochemistry was rare (5.4%). Ki67 baseline did not predict response. Conclusions: The addition of P to L increased by > 2 the PFS in pts who did not receive ST for their ER+ MBC. The most common AEs are manageable. Favorable risk benefit profile suggests P+L be considered for this group of pts. Clinical trial information: NCT00721409