PARP Inhibitor Demonstrates Clinical Activity in BRCA-Positive Patients

November 21, 2014

The poly (ADP-ribose) polymerase (PARP) inhibitor veliparib exhibits antitumor activity and is safe and tolerable on a continuous dosing schedule when used for the treatment of patients with BRCA-positive and BRCA–wild type tumors.

The poly (ADP-ribose) polymerase (PARP) inhibitor veliparib exhibits antitumor activity and is 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 ASCO Breast Cancer Symposium. Abstract 135

Veliparib is an oral small-molecule inhibitor of PARP 1 and PARP 2. “BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors,” 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.”

This phase I study was 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.

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 BRCApositive 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 flu-like symptoms.

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%.

Nurse Perspective

Janice Famorca Tran, RN, MS, AOCNP, CBCN, ANP-C

Texas Oncology Houston, TX

PARP inhibitors have demonstrated promising results in patients with BRCA mutation—related breast and ovarian cancers. The study performed by Pahuja et al, however, revealed the effectiveness of this type of medication in both BRCA-positive and BRCA-wild type patients. The study revealed that the PARP inhibitor veliparib, when used as single agent, was responsive in both BRCA-positive and BRCA-wild type tumors compared with other single-agent PARP inhibitors.

Normal cells use PARP to repair themselves; however, cancer cells may use PARP to repair DNA damage, therefore prolonging their uncontrolled growth. This abnormality can subsequently cause resistance to treatment. PARP inhibitors work to prevent repair of damaged DNA of cancer cells.

Veliparib is another addition to the growing understanding of the science of breast and ovarian cancer, and knowing upfront which patients would benefit from these drugs is another positive step towards personalized medicine.