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Veliparib fails to significantly extend survival in BRCA–mutated locally recurrent or metastatic breast cancer
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SAN ANTONIO — The addition of veliparib to carboplatin and paclitaxel did not significantly extend PFS or OS in patients with patients with BRCA1– or BRCA2–mutated locally recurrent or metastatic breast cancer, according to results of a randomized phase 2 study presented at San Antonio Breast Cancer Symposium.
However, the combination significantly increased overall response rate.
“We are very excited ... about the results that suggest tolerability and promising efficacy,” researcher Hyo Sook Han, MD, associate member at Moffitt Cancer Center in Tampa, Florida, said during a press conference. “We did not meet the primary endpoint, but the trend toward improved PFS and OS is definitely encouraging.”
An ongoing phase 3 trial likely will provide definitive answers about the utility of the combination, Han said.
Veliparib (ABT-888, AbbVie), a selective inhibitor of PARP-1 and PARP-2, has shown antitumor activity in phase 1 and phase 2 trials as monotherapy for patients with BRCA–positive breast cancer. The combination of veliparib and carboplatin/paclitaxel has demonstrated clinical activity and acceptable toxicity in phase 1 trials of patients with breast cancer.
The BROCADE study was the first randomized phase 2 trial to compare the addition of veliparib or placebo to carboplatin/paclitaxel in patients with locally recurrent or metastatic breast cancer who harbored BRCA1 or BRCA2 mutations.
The analysis included 290 patients treated at 86 sites in 20 countries. All patients had received two or fewer lines of chemotherapy for metastatic disease. They had not received prior platinum or PARP inhibitor treatment, and they did not have central nervous system metastases.
Researchers randomly assigned patients to one of three regimens administered in 28-day cycles:
- veliparib 120 mg twice daily on days 1 through 7, plus carboplatin area under the curve 6 and paclitaxel 175 mg/m2 every 3 weeks (n = 97);
- placebo plus the same carboplatin/paclitaxel regimen (n = 99); or
- veliparib 40 mg twice daily on days 1 through 7 plus temozolomide 150 to 200 mg/m2 once daily on days 1 through 5 (n = 94).
Treatment continued until progression or unmanageable toxicity.
Han presented results of the first two treatment groups. The cohorts were balanced with regard to median age; ER, PR and HER-2–negative status; ECOG performance status; and number of prior cytotoxic therapy regimens.
Results showed no significant difference in median PFS — the study’s primary endpoint — between the veliparib and placebo groups (14.1 months vs. 12.3 months; HR = 0.78; 95% CI, 0.53-1.16). Researchers reported no significant difference in median OS between groups (28.3 months vs. 25.9 months; HR = 0.75; 95% CI, 0.5-1.11). However, OS data are not yet mature, Han said.
The addition of veliparib significantly improved overall response rate (77.8% vs. 61.3%; P = .027). A higher percentage of patients assigned veliparib achieved complete response (5.6% vs. 3.8%) or partial response (72.2% vs. 57.5%).
Researchers also reported a higher clinical benefit rate (90.7% vs. 87%) and longer median duration of response (11.7 months vs. 11.1 months) with veliparib.
Patients assigned veliparib experienced higher rates of any-grade adverse events (100% vs. 97.9%) and serious adverse events (34.4% vs. 27.1%).
Veliparib-treated patients experienced higher rates of certain grade 3 to grade 4 hematologic adverse events, including neutropenia (55.9% vs. 55.2% for placebo), thrombocytopenia (31.2% vs. 26%), leukopenia (16.1% vs. 11.5%) and febrile neutropenia (8.6% vs. 3.1%). Patients assigned placebo were more likely to experience grade 3 to grade 4 anemia (17.7% vs. 17.2%).
Patients assigned veliparib and placebo experienced comparable rates of adverse events that required treatment interruption (75.3% vs. 71.9%), reduction (5.4% vs. 10.4%) or discontinuation (28% vs. 20.8%). – by Mark Leiser
Reference:
Han HSS. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio.
Disclosure: Han reports research funding to her institution from AbbVie, Corcept, Incyte, Karyopharm, Merrimack, Prescient and TapImmune. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Virginia Kaklamani, MD
A few years ago, we never used to do randomized phase 2 clinical trials. We would do phase 1 trials that were dose finding, phase 2 trials that were giving us just a hint of efficacy, and then large phase 3 trials that were definitive. We have moved a bit toward randomized phase 2 trials.
[These survival results] should not deter us from pursuing a potentially interesting medication. You saw some of the data on response rates. We don’t talk much about response rate, but if you are a patient and you have symptoms — for example, if you have lung metastasis and you’re coughing — and you receive a combination that produces a response and that cough goes away, your quality of life suddenly improves significantly. Although the FDA doesn’t look at response rate much, it is extremely clinically meaningful for our patients who are symptomatic. This is a good combination, but the caution is that we have to have a phase 3 trial to see whether it works. In that phase 3 clinical trial, I’d like to see more than just an improvement in response rate to be able to approve this medication. It definitely needs at least a PFS benefit.
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