Shalu Pahuja, MD
The PARP inhibitor veliparib is active, safe, and tolerable on a continuous dosing schedule when used for the treatment of patients with BRCA-positive and BRCA-wild type tumors. Data from a phase I trial indicate better clinical activity in patients with BRCA-positive tumors and a recommended phase II dose of 400 mg twice daily, said Shalu Pahuja, MD, at the 2014 Breast Cancer Symposium.
Veliparib is an oral small molecule inhibitor of PARP-1 and PARP-2. “BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors because cells with BRCA mutation are deficient in homologous recombination, which is a double-strand DNA repair pathway,” said Pahuja, an oncology fellow at the University of Pittsburgh Cancer Institute. PARP inhibitors exploit these alterations in DNA repair, as outlined by the concept of “synthetic lethality.”
There are phenotypic and genotypic similarities between BRCA-mutated tumors, basal-like breast cancers, and serous ovarian cancers. A potential mechanism to account for these similarities is BRCA promoter methylation. For this reason, these tumor types may be similarly sensitive to single agent PARP inhibition, forming the basis for this phase I study conducted in two cohorts of patients: a cohort with a documented BRCA 1/2 mutation (BRCA-positive cohort) and a BRCA-wild type cohort consisting of patients with triple-negative breast cancer or platinum-refractory ovarian, fallopian tube, or primary peritoneal cancer.
Veliparib was administered at escalating doses, starting at 50 mg twice daily up to 500 mg twice daily, to determine the maximum tolerated dose and a recommended phase II dose. Dose escalation was followed by enrollment to a dose expansion cohort at the recommended phase II dose (this cohort consisted only of BRCA-positive patients with mandatory serial biopsies).
At final enrollment, there were 70 BRCA-positive patients and 28 BRCA-wild type patients. In the wild type group, 86% of patients had triple-negative breast cancer, and 14% had ovarian cancer. In the BRCA-positive group, 23% had breast tumors, and 54% had ovarian tumors. Patients in the BRCA-positive group had a median of six prior treatments before enrollment, and those in the wild type group had a median of four.
There was no difference in the dose-limiting toxicities between the two groups. Dose-limiting toxicities included seizure at 400 mg twice daily in the wild type group and at 500 mg twice daily in the BRCA-positive group. There was one grade 3 incidence of nausea/vomiting at 400 mg twice daily in the BRCA-positive patients. Based on toxicities, 400 mg twice daily was recommended as the phase II dose.
No difference in the toxicity profiles was observed between the BRCA-positive versus BRCA-wild type patients. The most common all-grade toxicities were nausea, experienced by 37% of patients, lymphopenia (35%), fatigue (19%), and vomiting (9%). These were largely grade 1 or 2 toxicities. Forty percent of patients at the recommended phase II dose required dose reduction for low-grade nausea or flulike symptoms. There were no study drug-related deaths, but 12 deaths were reported due to disease progression.
Among the 24 BRCA-wild type patients (21 with breast tumors), “the triple-negative breast cancer patients received modest clinical benefit, including one patient with partial response and an additional eight patients with stable disease,” said Pahuja. There were too few patients with ovarian cancer in this cohort (n = 3) to draw conclusions.
“In contrast, clinical activity was greater in the BRCA-mutation cohort,” she said. “At all dose levels combined, the objective response rate [ORR] was 23% with a clinical benefit rate of 37% for all tumor types.”
Among patients with breast cancer in this cohort, the ORR was 29% with a 36% clinical benefit rate. In the patients with ovarian cancer, the ORR was 20% and the clinical benefit rate was 33%. Objective responses were more frequent at the higher dose levels: the ORR in BRCA-positive breast cancer patients and among all tumor types was approximately doubled at the two highest dose levels (400 mg and 500 mg twice daily) compared with the seven lower dose levels.
Pahuja S, Beumer JH, Appleman LJ, et al. Outcome of BRCA 1/2-mutated and triple-negative, BRCA wild type breast cancer patients in a phase I study of single-agent veliparib. J Clin Oncol. 2014;32(suppl 26; abstr 135).
<<< View more from the 2014 Breast Cancer Symposium