MILAN (EGMN) – Final results from an open-label phase II study confirm the survival advantage of adding an investigational PARP inhibitor to gemcitabine and carboplatin chemotherapy in metastatic triple-negative breast cancer.
Although not a prespecified outcome, median overall survival increased from 7.7 months to 12.3 months (hazard ratio, 0.57; P = .014,), lead author Dr. Joyce O’Shaughnessy reported in a late-breaking abstract at the the annual congress of the European Society for Medical Oncology. Median survival in this aggressive form of breast cancer is about 13 months after developing metastases.
Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine and carboplatin alone to 5.9 months with the addition of iniparib, a poly (adenosine diphosphate–ribose) polymerase-1 (PARP1) inhibitor also known as BSI-201 (HR, 0.59; P =.012).
The clinical benefit rate rose as well from 33.9% in the chemotherapy-alone arm to 55.7% in the iniparib arm (P = .015). This seemed to be driven by the overall response rate, which was 32.3% with chemotherapy alone and 52.5% with the addition of iniparib (P = .023). The clinical benefit rate (complete or partial response or stable disease for at least 6 months) was a coprimary end point with safety and tolerability.
Thirty of the 62 patients in the gemcitabine-carboplatin arm crossed over to receive iniparib plus chemotherapy. An unconfirmed partial response was reported in 1, stable disease in 4, and progressive disease in 18, while 7 were not evaluable.
The study’s rationale was that inhibiting PARP, an enzyme that helps the cell to repair DNA damage, would enhance the effectiveness of chemotherapy damaging DNA.
Dr. O’Shaughnessy reported on 123 women with estrogen receptor–, progesterone receptor– and HER2-negative breast cancer and a median of three metastatic sites who had received not more than two prior cytotoxic regimens. Of these, 62 were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (AUC = 2) IV on days 1 and 8 every 3 weeks, and 61 to the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11.
In a special PARP symposium at the meeting, chair Dr. Johann de Bono of the Royal Marsden Hospital and Institute of Cancer Research in Sutton, England, took issue with the study’s dosing. “I’m concerned that it was an insufficient dose of carboplatin in the control arm; was that the right dose to do – maybe. [But] was it even ethical?” he asked. “I think that’s a real key issue.”
When this concern was raised during the discussion of the study, Dr. O’Shaughnessy said they didn’t know for sure whether carboplatin AUC 5 or 6 given every 3 weeks in metastatic breast cancer would be superior. Indirect evidence from two phase II trials in unselected breast cancer patients showed response rates of 30% with carboplatin AUC 5 given every 3 weeks and with AUC 2.5 given every other week with gemcitabine 1,500 mg/m2.
“When we gave 2.5 every other week, after about two [to] three cycles, patients went down on their AUC to 2; that’s why we choose 2 as opposed to 2.5,” she said. “We couldn’t get the 2.5 in consistently.”
Invited discussant Dr. Richard Bell of the Andrew Love Cancer Centre in Geelong, Australia, said the difference in progression-free survival between study arms is clinically meaningful, but urged caution as the outcomes were investigator reported and other enthusiastically received phase II trials have fallen short in phase III evaluation.
“The big issue is would this work in other breast cancer types or in other cancer types,” he said.
A confirmatory phase III trial using the same schema has completed enrollment of 500 patients with triple-negative breast cancer, including women with BRCA mutations, said Dr. O’Shaughnessy. She noted that a recent study from M.D. Anderson Cancer Center found that 20% of 77 unselected triple-negative breast cancer patients carried a BRCA1/2 mutation.
Predictive biomarker evaluation is underway to identify subsets of triple-negative breast cancer patients likely to benefit from iniparib. Preoperative and adjuvant trials of iniparib in this setting are planned. Iniparib is also being studied in phase II and III trials in ovarian, uterine, and brain tumors.
Dr. Bell expressed surprise at the lack of toxicity reported with the addition of iniparib to chemotherapy. Although there is great excitement over the use of PARP inhibitors, with no less than 49 trials now in various stages, most have the potential to enhance toxicity, particularly hematologic toxicity, when used in combination with other drugs.
Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, said Dr. O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas. Grade 3 or 4 adverse events, mainly hematologic toxicity, were similar at 81% in the chemotherapy alone arm and 86% in the iniparib arm.
Grade 4 neutropenia occurred in 16 patients in each group; grade 4 thrombocytopenia in 10 in the chemotherapy group vs. 11 in the iniparib group. There were no grade 4 anemia or leukopenia events in either arm.
Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression, Dr. O’Shaughnessy said. In all, 14% in the iniparib group and 27% in the chemotherapy alone group discontinued treatment because of adverse events. Dose reductions were similar between study arms.
Dr. O’Shaughnessy reported no conflicts of interest. Several coinvestigators are employees of study sponsor Bipar Sciences Inc., which is developing iniparib with its parent company, Sanofi-Aventis.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
米兰(EGMN)——一项开放式Ⅱ期研究的最终结果证实了转移性三阴乳腺癌治疗中吉西他滨与卡铂联合化疗加用试验药PARP抑制剂的生存优势。
该研究共报告了123例雌激素受体、孕激素受体以及HER2阴性、转移部位中位数为3、既往接受不超过2种细胞毒性药物治疗方案的乳腺癌患者。其中，62例被随机分入吉西他滨(1,000 mg/m2 ，静脉注射)和卡铂(AUC=2，静脉注射)治疗组，在每3周的第1天和第8天用药，61例被随机分入同一化疗方案+iniparib治疗组，在第1、4、8和11天用药。
其结果显示，单用吉西他滨和卡铂治疗的中位无进展生存期为3.6个月，而加用iniparib(即BSI-201)——聚腺苷二磷酸核糖聚合酶-1(PARP1)抑制剂可使中位无进展生存期显著增至5.9个月(HR, 0.59; P=0.012)，使中位总生存期由7.7个月增至12.3个月(风险比，0.57；P=0.014)；临床收益率由33.9%增至55.7%(P=0.015)，总缓解率由32.3%升至52.5%(P =0.023)。临床收益率(完全或部分缓解或病情稳定持续至少6个月)是安全性和耐受性的复合主要终点。
吉西他滨和卡铂治疗组的62例中有30例换成接受iniparib+化疗治疗。其中1例报告部分缓解(未经证实)，4例报告病情稳定，18例报告病情进展，7例未能对病情进行评估。
单纯化疗组与化疗加用iniparib组的3级或4级不良事件(主要是血液学毒性)发生率相近，分别为81%和86%，4级血小板减少症的发生例数分别为10例对11例，死亡例数分别为1例对3例，均归因于病情进展，两组均未发生4级中性粒细胞减少症和4级贫血或白细胞减少事件。加用iniparib治疗组与单纯化疗组分别有14%和27%的患者因不良事件停止治疗。在剂量减少方面无组间差异。
化疗加用iniparib无毒性表现，iniparib的耐受性良好且未加重吉西他滨和卡铂的毒性，这令人叹为观止；加iniparib与单纯化疗组之间的无进展生存率差异具有临床意义，但对此也应审慎看待。
多个合作研究者在研究资助方Bipar Sciences公司(母公司为赛诺菲-安万特)任职。
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