Phase III Trial to Examine Veliparib in BRCA Positive Breast Cancer

Researchers are seeking to determine whether adding the PARP inhibitor valparib to a chemotherapy combination will improve outcomes for patients with HER2-negative, germline BRCA-associated metastatic or locally advanced breast cancer.

The international Brocade 3 trial, which is currently enrolling participants at more than 200 locations, seeks to randomize an estimated 500 patients in a 2:1 ratio to either veliparib with carboplatin and paclitaxel or a placebo plus the 2 chemotherapy agents (NCT02163694).

RATIONALE

“What we’re hoping to learn is whether, irrespective of hormonal status, the BRCA mutation is driving the response, as opposed to other factors,” explained principal investigator Shannon L. Puhalla, MD, who is director of the breast cancer clinical research program at the University of Pittsburgh Cancer Institute.

If successful, the addition of veliparib to a chemotherapy regimen would provide another option for a sizable subgroup of patients with the mutation Germline BRCA1 and BRCA2 mutations account for 5% to 10% of all breast cancers, from 20% to 25% of hereditary breast cancers. "Where this study will fill a void is for the patients who requires chemotherapy but also has a BRCA mutation,” said Puhalla. “Then there would be an advantage to giving the PARP inhibitor with chemotherapy.”

Nearly 78% of patients who were treated with a combination of veliparib and carboplatin/paclitaxel responded to treatment in phase II clinical trial results presented at the 2016 San Antonio Breast Cancer Symposium. However, progression-free survival (PFS) and overall survival (OS) did not meet the threshold for statistically significant improvement compared with the same chemotherapy regimen plus placebo.

Puhalla and colleagues believe there were enough positive signals in the results to remain optimistic about the prospects for success in the Brocade 3 study, however.

The phase II study also demonstrated that the backbone treatment of carboplatin and paclitaxel is extremely effective as first- or second-line therapy for patients who are BRCA mutation carriers.

TRIAL DESIGN

Participants will be randomized 2:1 to veliparib plus paclitaxel/carboplatin or placebo with the combination chemotherapy.

The phase III trial allows for veliparib/ placebo monotherapy (depending on which arm the patient is on) if there is toxicity with combination treatment, a difference between the phase II and II trials. The primary endpoint is PFS; secondary endpoints include OS, clinical benefit rate, and objective response rate. Upon confirmation of progression, patients randomized to placebo will have the option to crossover to receive single-agent veliparib.

WHO IS ELIGIBLE?

Women and men ≥18, with locally advanced (unresectable) or metastatic HER2-negative breast cancer who have a deleterious BRCA1 or BRCA2 germline mutation, ≤2 prior lines of DNA-damaging therapy, and stable CNS metastases are eligible for the trial.

The Brocade 3 trial is being conducted by AbbVie, which is also the company developing the drug. The study is expected to be completed in March 2018.