Prognosis of metastatic TNBC is poorer compared with those of other subtypes, because of the lack of effective treatment target. TNBC contains molecularly heterogeneous phenotypes, some of which are influenced by germline (g) BRCA1/2 mutation. Eribulin is one of standard treatments for metastatic TNBC and olaparib (Lymparza™), a PARP (poly ADP ribose polymerase) inhibitor, has shown remarkable efficacy in BRCA mutated breast cancer. Therefore, we evaluated the efficacy and safety of the combination of these drugs in a phase I/II trial (UMIN00009498) with an expectation of synergistic effect.
In phase I, we have determined the recommended dose as 300mg bid of olaparib twice daily and 1.4 mg/m2 of eribulin intravenously on day 1 and 8 in 21-day cycle. The primary efficacy endpoint in phase II was tumor response rate (RR) in the central review. The planned size was 24, with one-sided alpha of 0.1, power of 0.8, expected RR of 0.3 and threshold of 0.1.
Twenty-four patients were enrolled from June 2014 to December 2014 in phase II. The median age was 46 years old (range: 27 to 73). The median number of prior chemotherapy regimens was 3 (range: 2 to 6). Sixteen patients (66.7%) had visceral metastasis and 8 had non visceral metastasis. Dose intensity of eribulin was 0.69 (mg/m2·week) and that of olaparib was 2086.2 (mg/week). RR in central review was 29.2% (80%CI: 17.0-44.2), including 7 with PR, 7 with SD, 7 with PD and 3 with NE; thus, the null hypothesis was rejected. In institutional decision, RR was 37.5% (9/24; 95%CI, 18.8-59.4), including1 patient with CR. Median progression-free survival was 4.2 months (95%CI: 3.0 to 7.4). Median overall survival was 14.5 months (95%CI: 4.8 to 22.0). Safety was analyzed separately for phase I and II. Significant severe adverse events ( > =G3) were leukocytopenia (87.5%, 83.3%), neutropenia (87.5%, 83.3%), febrile neutropenia (20.8%, 33.3%), anemia (16.7%, 41.7%) and thrombosis (0%, 8.3%), respectively.
The combination of olaparib and eribulin was well tolerated and showed a promising efficacy and safety for metastatic TNBC.
Clinical trial identification
release date: 31/March/2017 (in Japanese)
Legal entity responsible for the study
National Cancer Hospital () National Cancer Center National Cancer Center
Exploratory Oncology Research & Clinical Trial Center in National Cancer Center
K. Aogi: Personal fees as honoraria from Eisai, AstraZeneca, Taiho Pharmaceutical, Daiichi Sankyo, Mochida Pharmaceutical, Ono Pharmaceutical, and Eli Lilly Japan. Research funds from Chugai Pharmaceutical, Eisai and Sanofi. K. Yonemori: Personal fee as honorarium from Eisai. M. Takahashi: Personal fees as honoraria from Chugai Pharmaceutical, Eisai, and AstraZeneca. N. Masuda: Personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca, and his institution received research funds from Chugai Pharmaceutical and Eisai. Y. Naito: Honoraria from Eisai, Chugai Pharmaceutical, Taiho Phamaceutical, Novartis Pharma, Eli Lilly Japan, Meiji Seika Pharma, and Bayer Yakuhin. He received research funds from Merck Serono, AstraZeneca, Eli Lilly Japan, and Nippon Kayaku. Y. Fujiwara: Honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, and Eli Lilly Japan. He received grants from Taiho, Takeda, Chugai, Eli Lilly Japan, and Nippon Kayaku. All other authors have declared no conflicts of interest.