Adding the investigational PARP inhibitor iniparib to the chemotherapy doublet gemcitabine/carboplatin significantly extended survival in metastatic triple-negative breast cancer in a phase II study involving 123 women.
Progression-free survival increased from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin to 5.9 months with chemotherapy plus iniparib.
Dr. Joyce A. O'Shaughnessy
Women who received the combination regimen lived nearly 5 months longer – a median of 12.3 months vs. 7.7 months for those receiving chemotherapy alone, Dr. Joyce O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas, and her associates reported (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMoa1011418]).
The primary efficacy end point of rate of clinical benefit, a measure of complete or partial response or stable disease for at least 6 months, was 34% in the chemotherapy arm vs. 56% in the iniparib arm.
Iniparib also significantly improved the overall response rate from 32% to 52%, suggesting that it may overcome the intrinsic drug resistance of some triple-negative breast cancers, the investigators reported. No standard-of-care therapy currently exists for patients with triple-negative breast cancer, a subgroup that represents 10%-15% of all breast cancer cases.
Iniparib inhibits poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), a key regulator of the DNA repair pathway, thereby enhancing the cytotoxic effects of chemotherapy.
If the phase II results are confirmed in a larger, ongoing phase III trial involving 500 women, PARP inhibition could be a rational approach to treating triple-negative breast cancer and the first therapy showing a survival advantage over chemotherapy alone, Dr. Lisa A. Carey and Dr. Norman E. Sharpless wrote in an accompanying editorial (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMe1012546]).
Although the results warrant excitement, the editorialists also urged caution. They pointed out that the cohort was small, the end points were investigator assessed, the chemotherapy regimen is unconventional, and there were imbalances in important prognostic factors favoring the iniparib group. It was also unclear whether the benefit of iniparib accrued to all triple-negative tumors equally or whether responders are mostly BRCA-positive patients, a smaller subset of triple-negative breast cancer.
"Caveats notwithstanding, these are exciting results presaging improved therapy for an underserved subgroup of patients with breast cancer and, we hope, heralding a new approach of ‘setting cancers up for the next blow’ by combining cytotoxic chemotherapy with agents directly targeting the DNA-damage response," wrote Dr. Carey and Dr. Sharpless, both with the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
The study enrolled 123 women with estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative breast cancer and a median of three metastatic sites; they had received no more than two prior cytotoxic regimens for metastatic disease. In all, 62 women were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (area under the curve [AUC] = 2) IV on days 1 and 8 every 3 weeks and 61 women received the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11. Twenty women initially received iniparib at a dose of 4.0 mg/kg IV, but the study protocol was amended in 2008 to reflect emerging phase I safety data.
During a formal presentation of the data at the 2010 congress of the European Society for Medical Oncology in Milan, concerns were raised over whether the control arm received an insufficient dose of carboplatin. Dr. O’Shaughnessy responded that they chose an AUC of 2 rather than 2.5 because they couldn’t administer carboplatin AUC 2.5 consistently.
[PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival]
Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, she reported. The incidence of grade 3 or 4 adverse events was 81% in the chemotherapy-alone arm vs. 86% in the iniparib arm. Notably, patients in the iniparib arm completed more treatment cycles (seven) than those in the chemotherapy-alone arm (four). Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression within 30 days of treatment.
One of the important questions remaining from the open-label trial is whether the activity of iniparib results from PARP inhibition or an unknown mechanism, Dr. Carey and Dr. Sharpless wrote. They raised the question because other PARP inhibitors have not shown promising results outside of BRCA-associated breast cancer, iniparib produced reduced toxicity compared with other PARP inhibitors when combined with chemotherapy, and iniparib is a much less potent inhibitor of PARP1 than most other agents of this class, with approximately 0.1% the potency.
There are also outstanding questions as to whether PARP inhibitors can enhance the effects of chemotherapy administered to other breast cancer subtypes or other tumor types, which chemotherapy regimens best synergize with PARP inhibitors, and whether PARP inhibitors may exhibit as yet unknown "on-target" toxic effects such as the diet-induced obesity and insulin resistance seen in PARP1-deficient mice.