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Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial
- Source :
- Lancet Oncology, 21(10), 1269-1282. ELSEVIER SCIENCE INC, Lancet Oncology, Lancet Oncology, Elsevier, 2020, 21, pp.1269-1282. ⟨10.1016/S1470-2045(20)30447-2⟩, Diéras, V, Han, H S, Kaufman, B, Wildiers, H, Friedlander, M, Ayoub, J P, Puhalla, S L, Bondarenko, I, Campone, M, Jakobsen, E H, Jalving, M, Oprean, C, Palácová, M, Park, Y H, Shparyk, Y, Yañez, E, Khandelwal, N, Kundu, M G, Dudley, M, Ratajczak, C K, Maag, D & Arun, B K 2020, ' Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3) : a randomised, double-blind, placebo-controlled, phase 3 trial ', The Lancet Oncology, vol. 21, no. 10, pp. 1269-1282 . https://doi.org/10.1016/S1470-2045(20)30447-2
- Publication Year :
- 2020
-
Abstract
- BACKGROUND: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.METHODS: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.FINDINGS: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.INTERPRETATION: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.FUNDING: AbbVie.
- Subjects :
- 0301 basic medicine
Oncology
Adult
Male
medicine.medical_specialty
Veliparib
Drug-Related Side Effects and Adverse Reactions
Organoplatinum Compounds
Paclitaxel
[SDV]Life Sciences [q-bio]
Population
Genes, BRCA2
Genes, BRCA1
Breast Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Placebo
Drug Administration Schedule
Carboplatin
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Breast cancer
Double-Blind Method
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Progression-free survival
education
Germ-Line Mutation
education.field_of_study
business.industry
BRCA mutation
Middle Aged
medicine.disease
Progression-Free Survival
3. Good health
030104 developmental biology
Treatment Outcome
chemistry
Response Evaluation Criteria in Solid Tumors
030220 oncology & carcinogenesis
Benzimidazoles
Female
business
Subjects
Details
- Language :
- English
- ISSN :
- 14702045
- Database :
- OpenAIRE
- Journal :
- Lancet Oncology, 21(10), 1269-1282. ELSEVIER SCIENCE INC, Lancet Oncology, Lancet Oncology, Elsevier, 2020, 21, pp.1269-1282. ⟨10.1016/S1470-2045(20)30447-2⟩, Diéras, V, Han, H S, Kaufman, B, Wildiers, H, Friedlander, M, Ayoub, J P, Puhalla, S L, Bondarenko, I, Campone, M, Jakobsen, E H, Jalving, M, Oprean, C, Palácová, M, Park, Y H, Shparyk, Y, Yañez, E, Khandelwal, N, Kundu, M G, Dudley, M, Ratajczak, C K, Maag, D & Arun, B K 2020, ' Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3) : a randomised, double-blind, placebo-controlled, phase 3 trial ', The Lancet Oncology, vol. 21, no. 10, pp. 1269-1282 . https://doi.org/10.1016/S1470-2045(20)30447-2
- Accession number :
- edsair.doi.dedup.....6b18c4df7a7a8a391ea38d376c5a98ec