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Veliparib active in BRCA-mutated breast cancer
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SAN FRANCISCO — Veliparib demonstrated anti-tumor activity comparable to that of other PARP inhibitors in patients with BRCA1 or BRCA2 mutations, according to results of a phase 1 study presented at the Breast Cancer Symposium.
Prior investigations have suggested PARP inhibitors are effective treatments for BRCA-mutated malignancies.
In the current study, Shalu Pahuja, MD, of the University of Pittsburgh Cancer Institute, and colleagues evaluated single-agent veliparib (ABT-888, AbbVie) — a potent oral inhibitor of PARP-1 and PARP-2 — in patients with BRCA-mutated and BRCA wild-type triple-negative breast cancer and serous ovarian cancer.
Pahuja and colleagues aimed to evaluate preliminary efficacy of the treatment, as well as to establish the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic and pharmocodynamic properties.
Pahuja and colleagues performed a 3+3 dose-escalation trial. They planned nine dose levels. Dose escalation began at 50 mg twice daily and peaked at 500 mg twice daily. Oral veliparib was administered continuously in 28-day cycles.
The analysis included 98 patients. Seventy patients with BRCA mutations were enrolled in one cohort. Twenty-eight patients with BRCA wild-type disease were enrolled in a second cohort.
Each cohort had separate dose escalations. For both cohorts, the maximum administered dose was 500 mg twice daily, and the maximum tolerated dose — recommended for phase 2 trials — was 400 mg twice daily.
Eighty-three patients were evaluable for response. They included 14 with BRCA-positive breast cancer, 35 with BRCA-positive ovarian cancer, 21 with BRCA wild-type breast cancer and three with BRCA wild-type ovarian cancer.
Researchers defined overall response rate as complete response plus partial response. Clinical benefit rate was defined as complete response, partial response and stable disease for longer than 6 months.
Researchers reported total overall response rates of 24% (14 of 59) among all BRCA-positive patients, 29% (4 of 14) among patients with BRCA-positive breast cancer, 4% (1 of 24) among all BRCA wild-type patients and 5% (1 of 21) among those with BRCA wild-type breast cancer.
Overall response rates to the maximum administered dose were 37% (13 of 35) among all BRCA-positive patients, 60% (3 of 5) among patients with BRCA-positive breast cancer, 0% (0 of 5) among all BRCA wild-type patients and 0% (0 of 4) among patients with BRCA wild-type breast cancer.
The total clinical benefit rate was 56% (33 of 59) among all BRCA-positive patients, 57% (8 of 14) among patients with BRCA-positive breast cancer, 17% (4 of 24) among all BRCA wild-type patients and 19% (4 of 21) among patients with BRCA wild-type breast cancer.
The clinical benefit rate observed with the maximum administered dose was 63% (22 of 35) among all BRCA-positive patients, 80% (4 of 5) among patients with BRCA-positive breast cancer, 0% (0 of 5) among all BRCA wild-type patients and 0% (0 of 4) among patients with BRCA wild-type breast cancer.
“There is evidence of anti-tumor activity with veliparib comparable to that of other PARP inhibitors in the BRCA-positive population,” Pahuja and colleagues wrote. “There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly triple-negative breast cancer, BRCA wild-type population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance.”
For more information:
Pahuja S. Abstract #135. Presented at: Breast Cancer Symposium; Sept. 4-6, 2014; San Francisco.
Disclosure: The researchers report employment/leadership positions with, stock ownership in or other interests in AbbVie and GlaxoSmithKline; consultant or advisory roles with Amgen, Celldex, Infinity Pharmaceuticals, Medimmune, Novartis and Pfizer; research funding from AbbVie, Bristol-Myers Squibb, Infinity Pharmaceuticals, Lilly, Millennium, Novartis, Pfizer, Saladax Biomedical, Spectrum Pharmaceuticals and Taiho Pharmaceutical; and honoraria from Pfizer.
Perspective
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Harold J. Burstein, MD, PhD
There has been mixed literature over the years about how important PARP inhibitors might be in triple-negative breast cancers. The work coming forward out of this abstract is very important because the investigators look carefully at the outcomes for patients with known BRCA mutations vs. those who had triple-negative breast cancer. Results show there are strong signals of activity, and those signals really are only seen in those women who have BRCA-associated cancers. Just having triple-negative breast cancer by itself does not seem to be enough to sensitize the tumor to the effect of the PARP inhibitors. Even though under the microscope triple-negative tumors often share a lot of features with hereditary BRCA-associated breast cancers — and even though many commentators talk about the BRCA-ness of triple-negative breast cancers — when it comes to therapeutics at the moment, these are clearly two different groups of women. It probably makes the most sense to focus the development of PARP inhibitors exclusively in those women who have BRCA1 or BRCA2 mutations.Click Here to Manage Email Alerts