Patients with advanced HER2-negative breast cancer and germline BRCA mutation demonstrated significantly improved progression-free survival (PFS) with the addition of the PARP inhibitor, veliparib to chemotherapy over placebo plus chemotherapy, according to findings presented at the ESMO Congress 2019 in Barcelona, Spain.
Véronique Diéras, Institut Curie, Paris, and Centre Eugène Marquis in Rennes, France reported findings from this double blind, placebo-controlled, phase III trial (NCT02163694) evaluating the efficacy of veliparib plus chemotherapy in patients with HER2-negative advanced/metastatic breast cancer and germline BRCA mutations.
Professor Diéras and colleagues reasoned that BRCA-mutated tumours are deficient in homologous recombination repair, making them susceptible to both platinum and PARP1/2 inhibitors, such as veliparib. Therefore, they randomised patients 2:1 to receive oral veliparib at 120 mg twice daily or placebo on days- 2 to 5, administered with carboplatin AUC 6 on day 1 and weekly paclitaxel at 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 at 300 to 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 2 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 (range, 24 to 82), 48% of patients were ER-negative/PgR–negative, and 4% had a history of CNS metastases.
Investigator assessed PFS served as the primary endpoint and secondary endpoints included overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR), and PFS2.
The study primary endpoint was met
Median PFS per investigator in 337 patients treated with veliparib plus chemotherapy was 14.5 months (95% confidence interval [CI], 12.5–17.7) compared to 12.6 months (95% CI, 10.6-14.4) in 172 patients receiving placebo plus chemotherapy (hazard ratio [HR] 0.71; 95% CI, 0.57-0.88; p = 0.002). Median PFS per independent review committee (IRC) was longer at 19.3 (95%) CI, 16.5- 23.3) months compared to 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% versus 11%.
BROCADE3 Primary Endpoint: PFS by Investigator Assessment.
© Véronique Diéras.
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 = 0.67).
CBR and ORR were high and similar between arms. At 24 weeks the CBR was 90.7% with veliparib and 93.2% with placebo, while ORR was 75.8% versus 74.1%.
However, prolonged PFS2 was seen with veliparib of 21.3 months (95% CI, 19.8-25.1) versus 17.4 months (95% CI, 16.0-20.0) with placebo, HR 0.76 (95% CI, 0.60-0.96).
The median duration of response was 14.7 months (95% CI, 12.1-18.7) versus 11.0 months (95% CI, 10.2-12.3), respectively.
The addition of veliparib did not substantially alter the toxicity profile of chemotherapy
Most of the patients in each treatment arm experienced an adverse event (AE) of special interest; all-grade AEs included neutropenia in 91% of patients in both arms, thrombocytopenia in 82% versus 72%, anaemia in 81% versus 70%, and nausea and vomiting in 75% versus 68% of patients in the veliparib versus placebo arms, respectively.
The most common study drug-related grade 3 and greater AEs occurring ≥20% of patients in the respective arms were anaemia (27% versus 17%), neutropenia (52% versus 50%), and thrombocytopenia (25% versus 15%).
Dose reductions of carboplatin were made for 88% of patients on veliparib with chemotherapy compared to 86% of patients receiving placebo with chemotherapy and 74% versus 70% had a paclitaxel dose reduction, respectively.
Conclusions
The investigators concluded that these findings demonstrated a significant improvement in PFS with veliparib, carboplatin and paclitaxel over placebo, carboplatin and paclitaxel. Median PFS for both arms was over 12 months. Furthermore, with veliparib, patients showed a durable benefit compared to control, 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
This study was funded by AbbVie.
Reference
LBA9 – Diéras VC, Han HS, Kaufman B, et al. Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer.