晚期乳腺癌哌柏西利一线最佳搭档
对于内分泌敏感、激素受体阳性、HER2阴性晚期乳腺癌，PALOMA-2研究已证实哌柏西利＋来曲唑显著优于来曲唑，故已成为标准一线治疗方案。同时，FALCON研究又证实氟维司群显著优于阿那曲唑。那么，哌柏西利＋氟维司群是否显著优于哌柏西利＋来曲唑？
2021年10月7日，《美国医学会杂志》肿瘤学分册在线发表西班牙、法国、英国、德国、意大利的PARSIFAL研究报告，对哌柏西利＋氟维司群于哌柏西利＋来曲唑一线治疗内分泌敏感、激素受体阳性、HER2阴性晚期乳腺癌的有效性和安全性进行了比较。
PARSIFAL (NCT02491983): Study to Evaluate the Efficacy and Safety of Palbociclib in Combination With Fulvestrant or Letrozole in Patients With ER+, HER2- Locally Advanced or Metastatic Breast Cancer (A Randomized, Multicenter, Open-label, Phase II Trial to Evaluate the Efficacy and Safety of Palbociclib in Combination With Fulvestrant or Letrozole in Patients With HER2 Negative, ER+ Metastatic Breast Cancer)
该国际多中心非盲随机对照二期临床研究于2015年7月30日～2018年1月8日从7个国家（西班牙、法国、意大利、英国、德国、捷克、俄罗斯）47个研究中心入组内分泌敏感、激素受体阳性、HER2阴性晚期乳腺癌女性患者486例（年龄25～90岁，中位63岁；亚洲女性3例，占0.6%；黑人女性4例，占0.8%；白人女性461例，占94.9%；未知种族女性18例，占3.7%）按1∶1的比例随机分为两组：哌柏西利＋氟维司群组243例、哌柏西利＋来曲唑组243例。2020年2月11日～5月15日进行数据分析。分层因素为疾病表现类型（新发与复发）和内脏转移状态（是与否）。主要终点为研究者根据实体瘤疗效评价标准1.1版评定的无进展生存。
结果，哌柏西利＋氟维司群组与哌柏西利＋来曲唑组相比：
中位无进展生存：27.9个月比32.8个月（95%置信区间：24.2～33.1、25.8～35.9个月）
进展或死亡风险：高13%（风险比：1.13；95%置信区间：0.89～1.45，P=0.32）
客观缓解率：46.5%比50.2%
3年总生存率：79.4%比77.1%
无论新发与复发、内脏转移与否，上述结果基本一致。
两个治疗组的3～4级不良事件发生率相似，并且未见新的安全问题，亦未报告治疗相关死亡。
因此，该研究结果表明，对于内分泌敏感、激素受体阳性、HER2阴性晚期乳腺癌患者，哌柏西利＋氟维司群与哌柏西利＋来曲唑相比，无进展生存并未改善，来曲唑仍然是此类患者一线治疗首选的哌柏西利最佳搭档。
相关链接
JAMA Oncol. 2021 Oct 7. Online ahead of print.
Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial.
Llombart-Cussac A, Pérez-García JM, Bellet M, Dalenc F, Gil-Gil M, Ruíz-Borrego M, Gavilá J, Sampayo-Cordero M, Aguirre E, Schmid P, Marmé F, Di Cosimo S, Gligorov J, Schneeweiss A, Albanell J, Zamora P, Wheatley D, Martínez-de Duenas E, Amillano K, Malfettone A, Cortés J; PARSIFAL Steering Committee and Trial Investigators.
Hospital Arnau de Vilanova, Universidad Católica, Valencia, Spain; Fundación Instituto Valenciano de Oncología, Valencia, Spain; Medica Scientia Innovation Research, Barcelona, Spain; Vall d'Hebrón Institute of Oncology, Vall d'Hebrón University Hospital, Barcelona, Spain; Institut Català d'Oncología, Insitut d'Investigació Biomèdica Bellvitge, Barcelona, Spain; Hospital del Mar Research Institute, Barcelona, Spain; Hospital del Mar, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Vall d'Hebrón Institute of Oncology, Barcelona, Spain; International Breast Cancer Center Quiron Group, Barcelona, Spain; Hospital Universitario Virgen del Rocío, Sevilla, Spain; Centro de Investigación Biomédica en Red de Oncología, Madrid, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Provincial Castellón, Castelló De La Plana, Spain; Hospital Universitari Sant Joan de Reus, Reus, Spain; Medica Scientia Innovation Research, Ridgewood, New Jersey; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Centre de recherches en cancérologie, Inserm, Toulouse, France; Institut Universitaire de Cancérologie Assistance Publique-Hopitaux de Paris, Sorbonne Université, Paris, France; Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, and Barts Hospital, NHS Trust, London, United Kingdom; Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom; University Hospital Heidelberg, Medical Faculty Mannheim Heidelberg University, Heidelberg, Germany; National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milano, Italy.
This randomized clinical trial investigates fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative breast cancer.
QUESTION: Which is the optimal endocrine partner (fulvestrant vs letrozole) for cyclin-dependent kinase 4 and 6 inhibitor palbociclib in previously untreated, endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer?
FINDINGS: In this randomized, open-label, phase 2 trial, 486 patients were assigned in equal numbers to receive palbociclib plus fulvestrant or letrozole. Median investigator-assessed progression-free survival was 27.9 months for fulvestrant-palbociclib vs 32.8 months for letrozole-palbociclib, a difference that was not statistically significant.
MEANING: Fulvestrant-palbociclib demonstrated no improvement in progression-free survival over letrozole-palbociclib, confirming letrozole as the preferred palbociclib partner in this patient population.
IMPORTANCE: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population.
OBJECTIVE: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario.
DESIGN, SETTING, AND PARTICIPANTS: In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020.
INTERVENTIONS: Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no).
MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1.
RESULTS: A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported.
CONCLUSIONS AND RELEVANCE: Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02491983
PMID: 34617955
DOI: 10.1001/jamaoncol.2021.4301