MILAN – 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.
Dr. Joyce O'Shaughnessy
Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine (Gemzar) 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.