Abstract P4-13-01: PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety
Authors: Cristofanilli M , Bondarenko I , Ro J , Im S-A , Masuda N , Colleoni M , DeMichele AM , Loi S , Verma S , Iwata H , Huang Bartlett C , Zhang K , Puyana Theall K , Turner NC , Slamon DJ 
Published: May 2016

Abstract
Background: Selective estrogen receptor modulators and aromatase inhibitors (AI) (+LHRH agonists [premenopausal]) are standard of care (SOC) for hormone–receptor–positive (HR+) metastatic breast cancer (MBC). Many HR+ MBC patients (pts) get limited benefit from adjuvant or advanced endocrine therapy (ET) and develop endocrine resistance, refractory disease. HR+ BC growth relies on cyclin dependent kinases 4/6 that promote G1–S phase cell cycle progression. Palbociclib (PAL) with ET showed efficacy in HR+/HER2– MBC (Turner et al, 2015). We report updated safety and efficacy from PALOMA3 with longer follow–up, focusing on degrees of clinically defined endocrine resistance.
Methods: Pts with HR+/HER2– MBC that progressed on prior ET were randomized 2:1 to PAL (125 mg/d oral [3 wks drug, 1 wk off]) + fulvestrant (F, 500 mg, SOC) +/– goserelin or placebo (PLB)+F. One line of chemotherapy (CT) for MBC was allowed. Pt stratification: prior ET sensitivity; visceral metastases; menopausal status. Primary endpoint (EP) was investigator–assessed progression–free survival (PFS). Secondary EP: overall survival, response assessment, patient–reported outcomes, safety.
Results: By March 2015, median follow–up was 8.9 mo. 521 pts were randomized (PAL+F, 347; PLB+F, 174). Baseline characteristics were balanced. Median PFS was 9.5 (95% CI 9.2–11.0) mo (PAL+F) vs 4.6 (3.5–5.6) mo (PLB+F) (HR 0.46 [0.36–0.59], P&lt;0.001). Overall response (CR+ PR) was significantly improved with PAL+F (ITT: 19% vs 8.6%, P=0.001; pts with measurable disease: 24.6% vs 10.9%, P&lt;0.001). Clinical benefit (CBR=CR+PR+SD ?24wks) was 66.6% vs 39.7% (P&lt;0.001). Benefit from PAL was confirmed in pre– and postmenopausal pts with PFS in premenopausal 9.5 vs 5.6 mo (HR=0.50 [0.29–0.87], P=0.006) and in postmenopausal 9.9 vs 3.9 mo (HR=0.45 [0.34–0.59], P&lt;0.001). Common adverse events (AEs) for PAL+F vs PLB+F were neutropenia (80.9 vs 3.5%), leukopenia (49.6 vs 4.1%), and fatigue (39.1 vs 28.5%); febrile neutropenia occurred in 0.9% (P+ F) vs 0.6% pts (PLB+F). Discontinuation due to AEs was 4.0% on P vs 1.7% on PLB. The benefit of PAL+F vs PLB+F was compared in pts with various degrees of endocrine resistance: a) progression ≤12 mo of adjuvant ET completion, PFS 9.5 vs 5.4 mo (HR 0.55 [0.32–0.92], P=0.01); b) failed 1 line of ET, 10.2 vs 5.4 mo (HR 0.42 [0.29–0.59], P&lt;0.001); c) failed 2 lines of ET, 9.9 vs 1.8 mo (HR=0.20 [0.10– 0.39, P&lt;0.001); d) proven endocrine sensitive, 10.2 vs 4.2 mo (HR 0.42 [0.32–0.56], P&lt;0.001); e) proven no prior endocrine sensitivity, 7.5 vs 5.4 mo (HR 0.64 [0.39–1.07], P=0.04) f) AI most recent therapy, 9.5 vs 3.7 mo (HR 0.42 [0.31–0.56], P&lt;0.001).
Conclusion: Mature efficacy confirmed superior PFS and demonstrated significantly improved clinical response and CBR by the combination of ET and Palbociclib. It also consistently showed therapeutic benefit irrespective of menopausal status and various degrees of endocrine sensitivity. Safety profile is favorable. PAL+F may be an effective option for HR+ MBC pts.
Funding: Pfizer.
Citation Format: Cristofanilli M, Bondarenko I, Ro J, Im S-A, Masuda N, Colleoni M, DeMichele AM, Loi S, Verma S, Iwata H, Huang Bartlett C, Zhang K, Puyana Theall K, Turner NC, Slamon DJ. PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-01.