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ESMO 2019: BROCADE 3: Veliparib Plus Carboplatin/Paclitaxel in Patients With HER2-Negative, Germline BRCA-Mutated Advanced Breast Cancer


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Patients with advanced or metastatic HER2-negative breast cancer with a germline BRCA mutation demonstrated significantly improved progression-free survival (PFS) with the addition of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to chemotherapy (comprised of carboplatin/paclitaxel) vs placebo plus chemotherapy, according to findings presented by Diéras et al at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract LBA9).

Véronique Diéras, MD, of Institut Curie and Centre Eugène Marquis, reported findings from the double blind, placebo-controlled, phase III trial. Dr. Diéras and colleagues reasoned that BRCA-mutated tumors are deficient in homologous recombination repair, making them susceptible to both platinum chemotherapy and PARP1/2 inhibitors, such as veliparib.

Methods

In the trial, patients were randomly assigned 2:1 to receive oral veliparib 120 mg twice daily or placebo on days 2 to 5, administered with carboplatin area under the curve 6 on day 1 and weekly paclitaxel 80 mg/m2 on days 1, 8, and 15 in 21-day cycles. Patients discontinuing both carboplatin and paclitaxel without disease progression received blinded single-agent veliparib 300–400 mg twice daily or placebo. Patients were treated until disease progression or unacceptable toxicity.

All patients had germline BRCA1/2 mutations and had previously received two or fewer lines of cytotoxic therapy for metastatic breast cancer; 8% of patients had received prior platinum therapy and 19% had received chemotherapy for metastatic disease. The median patient age was 47 years old; 48% of patients had estrogen receptor–negative/progesterone receptor–negative disease, and 4% had a history of central nervous system metastases.

The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival, clinical benefit rate (CBR), objective response rate (ORR), and time to second progression.

Results

Median PFS per investigator assessment in 337 patients treated with veliparib plus carboplatin/paclitaxel was 14.5 months (95% confidence interval [CI] =12.5–17.7) vs 12.6 months (95% CI = 10.6–14.4) in 172 patients receiving placebo/chemotherapy (hazard ratio [HR] = 0.71; 95% CI = 0.57–0.88; P = .002). Median PFS per independent review committee was longer at 19.3 (95% CI = 16.5–23.3) months vs 13.5 (95% CI = 12.5–16.3) months, respectively (HR = 0.70; 95% CI, 0.54-0.90). PFS at 3 years was doubled with veliparib; the respective cohorts demonstrated 3-year PFS rates of 26% vs 11%.

At the interim analysis, median OS was 33.5 (95% CI = 27.6–37.9) months with veliparib/chemotherapy compared to 28.2 (95% CI = 24.7–35.2) months with placebo/chemotherapy (HR = 0.95; 95% CI = 0.73–1.2, P = .67).

KEY POINTS

  • Median PFS per investigator assessment in 337 patients treated with veliparib plus carboplatin/paclitaxel was 14.5 months vs 12.6 months in 172 patients receiving placebo/chemotherapy.
  • At the interim analysis, median OS was 33.5 months with veliparib/chemotherapy compared to 28.2 months with placebo/chemotherapy.

CBR and ORR were high and were similar between the two arms. At 24 weeks, the CBR was 90.7% in the veliparib/chemotherapy arm and 93.2% in the placebo/chemotherapy arm, while ORR was 75.8% vs 74.1%. However, prolonged time to second progression was seen in the veliparib/chemotherapy arm—21.3 months (95% CI = 19.8–25.1) vs 17.4 months (95% CI = 16.0–20.0) in the placebo/chemotherapy arm (HR = 0.76; 95% CI = 0.60–0.96).

The median duration of response was 14.7 months (95% CI = 12.1–18.7) vs 11.0 months (95% CI = 10.2–12.3), respectively.

Most of the patients in each treatment arm experienced an adverse event of special interest; all-grade adverse events included neutropenia in 91% of patients in both arms, thrombocytopenia in 82% vs 72%, anemia in 81% vs 70%, and nausea and vomiting in 75% vs 68% of patients in the veliparib/chemotherapy vs placebo/chemotherapy arms, respectively. The most common study drug-related grade 3 and greater adverse events occurring in ≥ 20% of patients in the respective arms were anemia (27% vs 17%), neutropenia (52% vs 50%), and thrombocytopenia (25% vs 15%).

Dose reductions of carboplatin were made for 88% of patients treated with veliparib/chemotherapy compared to 86% of patients receiving placebo/chemotherapy, and 74% vs 70% had a paclitaxel dose reduction, respectively.

The investigators concluded that these findings demonstrated a significant improvement in PFS with veliparib plus carboplatin/paclitaxel over placebo plus carboplatin/paclitaxel. Median PFS for both arms was over 12 months. Furthermore, with veliparib, patients showed a durable benefit compared to the control group, with 26% of patients treated with veliparib remaining alive and progression-free at 3 years compared to just 11% of patients receiving placebo/chemotherapy.

 

Disclosure: BROCADE 3 was funded by AbbVie. For full disclosures of the study authors, visit esmo.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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