PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC).

507 Background: Hormonal therapy (HT) is the mainstay for patients (pts) with ER+ BC. P, a cyclin-dependent kinase 4/6 inhibitor, blocks growth of ER+/HER2– BC preclinical models. In PALOMA-1, an open-label Ph 2 trial, addition of P to L improved median PFS vs L alone (20.2 months [mo] vs 10.2 mo) in pts with first-line ER+/HER2– ABC with acceptable safety, leading to accelerated FDA approval. PALOMA-2 is a randomized double-blind Ph 3 trial designed to confirm these results. Methods: 666 postmenopausal pts with no prior systemic therapy for ABC were randomized 2:1 to receive P (oral 125 mg/d; 3 wks on/1 wk off) + L (2.5 mg/d continuously) or PLB + L every 28 days until disease progression, consent withdrawal or death. Pts were stratified by disease site, disease-free interval from end of (neo)adjuvant therapy, and prior HT (yes/no). Primary endpoint: investigator-assessed PFS; key secondary endpoints: overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR=CR + PR + SD ≥24 wks), patient-reported outcomes and safety. Tumor assessments were every 12 wks. 347 events were needed with 90% power to detect a hazard ratio (HR) ≤0.69 in favor of P+L (1-sided α=0.025). Results: By 26 Feb 2016, 331 PFS events occurred. Baseline characteristics were well balanced. Median PFS was 24.8 mo (P+L) vs 14.5 mo (PLB+L) (HR=0.58 [0.46–0.72], P<0.000001). ORR was improved with P+L (42.1% vs 34.7%, P=0.031; 55.3% vs 44.4% in pts with measurable disease [P=0.013]). CBR was 84.9% vs 70.3% (P<.0001). Common adverse events (AEs; all grades) with P+L vs PLB+L were neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%) and alopecia (32.9% vs 15.8%). Most common severity seen was G3 for neutropenia (56.1%) and G1 for the other AEs. Febrile neutropenia was seen only with P+L (2.5%). Permanent discontinuation due to AEs was 9.7% (P+L) vs 5.9% (PLB+L). OS data are immature; final OS analysis is pending. Conclusion: PALOMA-2 expands and confirms the significant clinical benefit and safety of P+L in ER+/HER2– ABC pts who had not received prior systemic therapy for their advanced disease. Clinical trial information: NCT01740427.