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

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<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<0.001). Clinical benefit (CBR=CR+PR+SD ?24wks) was 66.6% vs 39.7% (P<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<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<0.001); c) failed 2 lines of ET, 9.9 vs 1.8 mo (HR=0.20 [0.10– 0.39, P<0.001); d) proven endocrine sensitive, 10.2 vs 4.2 mo (HR 0.42 [0.32–0.56], P<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<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.

Preclinical Activity of Abemaciclib Alone or in Combination with Antimitotic and Targeted Therapies in Breast Cancer

“…The cyclin dependent kinases 4 and 6 (CDK4/6) are key regulators of the G1 to S-phase restriction checkpoint and pharmacologically targeting these proteins in combination with hormonal blockade has been shown to provide significant therapeutic benefit to patients with advanced ER+/HER2-breast cancer (13)(14)(15). In ER-dependent tumors, activated ER-signaling leads to increased transcription and synthesis of cyclin D1, promoting formation of activating complexes with CDK4/6 (16).…”

“…These data led to the clinical development and recent approval of palbociclib for use in ER+/HER2-metastatic breast cancer (13,(21)(22)(23)) and subsequently, a second CDK4/6 inhibitor, ribociclib in the same breast cancer subtype (15). Abemaciclib (LY2835219; Eli-Lilly) is also an orally available ATP-competitive inhibitor of CDK4 and CDK6, with single digit nanomolar potency against both kinases.…”

Cyclin-Dependent Kinase Inhibitor, Palbociclib – A New Drug for the Treatment of Metastatic Breast Cancer

“…В этой когорте медиана ВБП для комбинации палбоциклиб + фулвестрант на момент первичного анализа не была достигнута, для моноте-рапии фулвестрантом -соответствовала таковой по оценке исследователей (3,7 мес, ОР = 0,27; р <0,001) [26]. Обновленные результаты независимого слепого центрального контроля эффективности подтвердили статистически достоверное и клинически значимое увеличение ВБП при добавлении палбоциклиба к фул-вестранту по сравнению с одной ГТ [28].…”

“…В многоцентровом рандомизи-рованном плацебо-контролируемом исследовании III фазы PALOMA-3 оценивали эффективность и пе-реносимость комбинации палбоциклиб + фулвестрант по сравнению с одним фулвестрантом у больных HR-положительным HER2-отрицательным мРМЖ с прогрессированием на предшествующей ГТ (n = 521) [26][27][28].…”

“…В этой когорте медиана ВБП для комбинации палбоциклиб + фулвестрант на момент первичного анализа не была достигнута, для моноте-рапии фулвестрантом -соответствовала таковой по оценке исследователей (3,7 мес, ОР = 0,27; р <0,001) [26]. Обновленные результаты независимого слепого центрального контроля эффективности подтвердили статистически достоверное и клинически значимое увеличение ВБП при добавлении палбоциклиба к фул-вестранту по сравнению с одной ГТ [28].Очень важно то, что исходный менопаузальный ста-тус пациенток не влиял на эффективность лечения: вы-игрыш от добавления палбоциклиба в отношении ме-дианы ВБП был практически одинаковым у больных в пременопаузе / перименопаузе и постменопаузе (ОР = 0,44 и 0,41 соответственно), что поддерживает примене-ние указанной стратегии в широкой популяции больных HR-положительным мРМЖ. Кроме того, подгрупповой анализ продемонстрировал преимущество комбинации палбоциклиб + фулвестрант у пациенток с висцераль-ными и невисцеральными метастазами независимо от чувствительности к предшествующей ГТ, статуса PR, характера и числа линий предшествующей терапии.…”