• Veliparib是多聚ADP-核糖聚合酶抑制剂(PARPi),通过抑制DNA单链断裂的修复,导致BRCA缺陷的细胞死亡;
  • 本研究纳入BRCA1和BRCA2相关转移性乳腺癌(MBC)患者各22位,予veliparib单药治疗,有效率分别为14%和36%,中位无疾病进展生存时间和总生存时间分别为5.2和14.5个月;
  • Veliparib单药治疗后病情进展的30位患者,veliparib和卡铂联合治疗在1位中有效;
  • 外周血单个核细胞中高PAR水平与临床获益相关。

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer



2017-03-29, Article

Abstract & Authors:展开

PURPOSE: We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2-(BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment post-progression, and to correlate PAR levels with clinical outcome. <br /><br />Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID) and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. <br /><br />Results:Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia (MTD: veliparib 150 mg po BID and carboplatin [AUC of 5]). Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 phase II trial patients, with a 14% RR in BRCA1 (n=22) and 36% in BRCA2 (n=22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.<br /><br />Conclusions:Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.

First Authors:
George Somlo,Jeffrey N Weitzel

Correspondence Authors:
George Somlo,Jeffrey N Weitzel

All Authors:
George Somlo,Paul H Frankel,Banu K Arun,Cynthia X Ma,Agustin A Garcia,Tessa Cigler,Leah V Cream,Harold A Harvey,Joseph A Sparano,Rita Nanda,Helen K Chew,Timothy J Moynihan,Linda T Vahdat,Matthew P Goetz,Jan H Beumer,Arti Hurria,Joanne Mortimer,Richard Piekarz,Sharon Sand,Josef Herzog,Lily R Van Tongeren,Katherine V Ferry-Galow,Alice P Chen,Christopher Ruel,Edward M Newman,David R Gandara,Jeffrey N Weitzel