晚期乳腺癌基因突变患者靶向疗法
他拉唑帕利（他佐帕利、他拉唑帕）属于多腺苷二磷酸核糖聚合酶（PARP）抑制剂，1期和2期ABRAZO研究已经证实，他拉唑帕利对乳腺癌易感基因（BRCA）突变的晚期乳腺癌患者具有抗肿瘤活性。2016年8月22日，辉瑞斥资140亿美元收购了他拉唑帕利的研发者Medivation。
2018年8月15日，美国麻省医学会《新英格兰医学杂志》在线发表美国德克萨斯大学M.D.安德森癌症中心、贝勒医疗集团查尔斯萨蒙斯癌症中心、旧金山加利福尼亚大学综合癌症中心、辉瑞、洛杉矶加利福尼亚大学、北加利福尼亚凯泽永久医疗集团、班纳医疗集团M.D.安德森癌症中心、德国慕尼黑理工大学伊萨河右岸医院、慕尼黑多学科肿瘤中心、法国马赛保利卡尔梅特斯医院、图卢兹大学肿瘤医院、克劳迪斯雷加德医院、韩国首尔大学医院、成均馆大学三星首尔医院、以色列拉宾医疗中心贝林森医院、西班牙乳腺癌研究协作组、马德里大学附属医院的3期EMBRACA研究报告，比较了他拉唑帕利与标准化疗对晚期乳腺癌生殖系BRCA突变患者的有效性和安全性。
该国际多中心非盲随机对照3期研究于2013年10月～2017年4月从16个国家145个单位入组431例HER2阴性晚期乳腺癌生殖系BRCA突变患者，按2∶1随机分组，其中287例每天口服他拉唑帕利1mg，其余144例接受医师选择的标准单药化疗（卡培他滨、艾日布林、吉西他滨、长春瑞滨，连续21天）。主要研究终点为无进展生存，通过盲法独立集中复核进行评定。
结果发现他拉唑帕利与标准化疗相比：
中位无进展生存显著较长（8.6比5.6个月），进展或死亡风险减少46%（风险比：0.54，95%置信区间：0.41～0.71，P<0.001）
中期分析中位总生存较长（22.3比19.5个月），死亡风险减少24%（中位风险比：0.76，95%置信区间：0.55～1.06，P=0.11）
客观缓解率显著较高（62.6%比27.2%，比值比：5.0，95%置信区间：2.9～8.8，P<0.001）
血液学3～4级不良事件（主要为贫血）发生率分别为55%、38%
非血液学3级不良事件发生率分别为32%、38%
患者自评结局有利于他拉唑帕利；根据整体健康状况、生活质量和乳房症状量表，总体显著改善、有临床意义的恶化显著延迟。
因此，对于晚期乳腺癌生殖系BRCA1/2突变患者，他拉唑帕利单药与标准单药化疗相比，无进展生存显著获益，患者自评结局较好。
同日，欧洲肿瘤内科学会《肿瘤学年鉴》在线发表3期EMBRACA研究患者自评结局报告，比较了他拉唑帕利与标准化疗对晚期乳腺癌生殖系BRCA突变患者生活质量的影响。
N Engl J Med. 2018 Aug 15. [Epub ahead of print]
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
Jennifer K. Litton, Hope S. Rugo, Johannes Ettl, Sara A. Hurvitz, Anthony Goncalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi, Lida A. Mina, Miguel Martin, Henri Roché, Young-Hyuck Im, Ruben G.W. Quek, Denka Markova, Iulia C. Tudor, Alison L. Hannah, Wolfgang Eiermann, Joanne L. Blum.
University of Texas M.D. Anderson Cancer Center, Houston; Texas Oncology-Baylor Charles A. Sammons Cancer Center, US Oncology Network, Dallas, Texas; University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Pfizer, San Francisco, University of California, Los Angeles, Los Angeles; Kaiser Permanente, Northern California, Vallejo, California; Klinikum Rechts der Isar, Technische Universitat München; Interdisziplinares Onkologisches Zentrum München, Munich, Germany; Institut Paoli-Calmettes, Marseille; Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse, Toulouse, France; Seoul National University Hospital, Samsung Medical Center, Seoul, South Korea; Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Banner M.D. Anderson Cancer Center, Gilbert, AZ; Instituto de Investigación Sanitaria Gregorio Maranón, Centro de Investigación Biomédica en Red Oncología, Grupo Espanol de Investigación en Cáncer de Mama, Universidad Complutense, Madrid.
BACKGROUND: The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2).
METHODS: We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.
RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed.
CONCLUSIONS: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib.
FUNDING: Medivation [Pfizer]
CLINICALTRIALS.GOV: NCT01945775 (EMBRACA)
DOI: 10.1056/NEJMoa1802905
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