Addition of veliparib to platinum chemotherapy extends PFS in BRCA-mutated breast cancer
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The addition of veliparib to carboplatin and paclitaxel significantly improved PFS for patients with metastatic breast cancer who have germline BRCA mutations, according to randomized phase 3 study results presented at European Society for Medical Oncology Congress.
“Early studies of [poly(ADP)-ribose polymerase (PARP) inhibitors] in combination with platinum chemotherapy have been challenging due to exacerbation of myelosuppression, which may be the result of PARP trapping,” Vèronique Dieras, MD, clinical oncologist at Centre Eugenè Marquis Rennes in France, said during her presentation. “Veliparib potently inhibits PARP with minimal PARP trapping, which may allow for use in combination with platinum chemotherapy.”
The analysis included 509 patients (median age, 47 years; range, 24-82; 88% white) with germline BRCA1- or BRCA2-mutated metastatic breast cancer who underwent two prior lines of cytotoxic therapy for metastatic breast cancer.
Dieras and colleagues randomly assigned 337 of them to veliparib (ABT-888, AbbVie) dosed at 120 mg daily plus carboplatin and paclitaxel. The other 172 patients received placebo plus carboplatin and paclitaxel.
Nearly half (48%) of all patients had ER-negative/PR-negative disease, 8% received prior platinum therapy, 4% had a history of central nervous system metastases, and 19% received prior chemotherapy for metastatic disease.
PFS per investigator assessment served as the primary endpoint. OS, clinical benefit rate, objective response rate and PFS2 served as secondary endpoints.
Results showed a statistically significant benefit in median PFS by investigator assessment for patients who received veliparib (14.5 months vs. 12.6 months; HR = 0.71; 95% CI, 0.56-0.87). This translated to 3-year PFS rates of 26% for patients assigned veliparib and 13.5% for patients assigned placebo.
PFS by independent central review also showed a statistically significant benefit for patients who received veliparib (median, 19.3 months vs. 13.5 months; HR = 0.7; 95% CI, 0.54-0.9).
Veliparib also conferred benefits in median OS (33.5 months vs. 28.2 months; HR = 0.95; 95% CI, .73-1.2), ORR (75.8% vs. 74.1%), median PFS2 per investigator assessment (21.3 months vs. 17.4 months; HR = 0.76; 95% CI, 0.6-0.96) and median duration of response (14.7 months vs. 11 months).
The most common grade 3 or higher adverse events in in the veliparib and placebo groups were anemia (27% vs. 17%), neutropenia (52% vs. 50%) and thrombocytopenia (25% vs. 15%).
Numerically higher percentages of patients assigned veliparib required dose reductions in carboplatin (88% vs. 86%) and paclitaxel (74% vs. 70%).
“This regimen was well-tolerated... and it did not compromise the administration of chemotherapy,” Dieras said. “This should be a preferred treatment option going forward.” – by John DeRosier
Reference:
Dieras VC, et al. Abstract LBA9. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: AbbVie funded this study. Dièras reports consultant roles with AbbVie, Astellas, AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Genentech/Roche, Merck Sharpe & Dohme, Nektar Therapeutics, Odonate, Pfizer, Seattle Genetics and Tesaro. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Aditya Bardia, MD, MPH
This is an interesting study that demonstrated a very high response rate with the triplet combination, though the improvement in PFS was more modest (14.5 months versus 12.6 months).
Veliparib is a weak PARP trapper, which made it easier to combine with chemotherapy given the overlapping toxicity of myelosuppression seen with both chemotherapy and PARP inhibitors. Moving forward, it would be interesting to see whether oncologists would prefer to utilize a PARP inhibitor with chemotherapy instead of utilizing them sequentially for patients with germline BRCA mutations.
Given the adverse events and patient convenience with oral monotherapy, utilizing a PARP inhibitor alone would be appealing, but this decision ultimately requires consideration of patient preference and therapy goals. The authors and study team should be congratulated for successful execution of this important study.
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