Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial

Jean Pierre Ayoub; Hans Wildiers; Michael Friedlander; Banu K. Arun; Hyo S. Han; Shannon Puhalla; Yaroslav Shparyk; Erik H. Jakobsen; Meijing Wu; Bruce A. Bach; Dai Feng; Christine K. Ratajczak; David Maag; Véronique Diéras

doi:10.1177/17588359211059601

Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial

Jean Pierre Ayoub, Hans Wildiers, Michael Friedlander, Banu K. Arun, Hyo S. Han, Shannon Puhalla, Yaroslav Shparyk, Erik H. Jakobsen, Meijing Wu, Bruce A. Bach, Dai Feng, Christine K. Ratajczak, David Maag, Véronique Diéras^*

^*Kontaktforfatter

IRS - Sygehus Lillebælt, Forskningsenhed for Onkologi (Vejle)

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.

Originalsprog	Engelsk
Tidsskrift	Therapeutic Advances in Medical Oncology
Vol/bind	13
Sider (fra-til)	1-13
ISSN	1758-8340
DOI	https://doi.org/10.1177/17588359211059601
Status	Udgivet - dec. 2021

Bibliografisk note

Funding Information:
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JPA: Research funding (institution), AbbVie, Boston Biomedical; consultancy, AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer, Puma, Roche. HW: Consulting fees and honoraria (institution), Roche, AstraZeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex Therapeutics, Janssen-Cilag, TRM Oncology, PUMA Biotechnology, Orion Corporation; unrestricted research grant, Roche; travel support, Roche, Pfizer. MF: Consulting/advisory role, AstraZeneca, MSD, AbbVie, Lilly, GSK, Takeda; speakers’ bureau, AstraZeneca; honoraria, AstraZeneca, MSD, GSK, Lilly, Takeda, Novartis, ACT Genomics; travel/accommodation expenses, AstraZeneca; research funding, BeiGene, AstraZeneca, Novartis. BKA: Research support (institution), AbbVie, PharmaMar, AstraZeneca, Invitae; steering committee (nonpaid), AbbVie. HSH: Research funding (institutions), Arvinas, AbbVie, BMS, Daiichi Pharma, GSK, G1 Therapeutics, Horizon, Karyopharm, Marker Therapeutics, Novartis, Pfizer, Prescient, Seattle Genetics, Zymeworks; speakers’ bureau, Lilly. SLP: Consultant, AbbVie, MedImmune, Celldex, Puma, Pfizer, AstraZeneca, Eisai, NanoString; research funding to institution, AbbVie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, AstraZeneca, Genentech, Medivation. YS: Advisory board: Pfizer; speaker: Roche, AstraZeneca, Pfizer; research/clinical studies: AbbVie, Roche, MSD, Boehringer Ingelheim. EHJ: Consulting/advisory role: Pfizer, Roche, Novartis, Eli Lilly. BB: Former employee of AbbVie and may hold AbbVie stock. MW, DF, CKR, and DM: AbbVie employees and may own stock. VD: Consulting/advisory role, Roche/Genentech, Novartis, Lilly, Pfizer, AbbVie, MSD, Daiichi Sankyo, Seattle Genetics, AstraZeneca, Gilead.

Funding Information:
The authors thank all the trial investigators, including the late Dr Bella Kaufman, and the patients who participated in this clinical trial. Medical writing support was provided by Thayer Darling, PhD, from Aptitude Health, Atlanta, Georgia, and funded by AbbVie.

Publisher Copyright:
© The Author(s), 2021.

Dokumenter og links

10.1177/17588359211059601Licens: CC BY-NC

Open Access VersionForlagets udgivne version, 2,45 MBLicens: CC BY-NC

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Citationsformater

Ayoub, J. P., Wildiers, H., Friedlander, M., Arun, B. K., Han, H. S., Puhalla, S., Shparyk, Y., Jakobsen, E. H., Wu, M., Bach, B. A., Feng, D., Ratajczak, C. K., Maag, D., & Diéras, V. (2021). Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial. Therapeutic Advances in Medical Oncology, 13, 1-13. https://doi.org/10.1177/17588359211059601

Ayoub, Jean Pierre ; Wildiers, Hans ; Friedlander, Michael et al. / Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer : subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial. I: Therapeutic Advances in Medical Oncology. 2021 ; Bind 13. s. 1-13.

@article{37624175479c40e7a9eab040bad0c3f1,

title = "Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial",

abstract = "Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.",

keywords = "BRCA, breast cancer, PARP inhibitor, phase 3, TNBC",

author = "Ayoub, {Jean Pierre} and Hans Wildiers and Michael Friedlander and Arun, {Banu K.} and Han, {Hyo S.} and Shannon Puhalla and Yaroslav Shparyk and Jakobsen, {Erik H.} and Meijing Wu and Bach, {Bruce A.} and Dai Feng and Ratajczak, {Christine K.} and David Maag and V{\'e}ronique Di{\'e}ras",

note = "Publisher Copyright: {\textcopyright} The Author(s), 2021.",

year = "2021",

month = dec,

doi = "10.1177/17588359211059601",

language = "English",

volume = "13",

pages = "1--13",

journal = "Therapeutic Advances in Medical Oncology",

issn = "1758-8340",

publisher = "SAGE Publications",

}

Ayoub, JP, Wildiers, H, Friedlander, M, Arun, BK, Han, HS, Puhalla, S, Shparyk, Y, Jakobsen, EH, Wu, M, Bach, BA, Feng, D, Ratajczak, CK, Maag, D & Diéras, V 2021, 'Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial', Therapeutic Advances in Medical Oncology, bind 13, s. 1-13. https://doi.org/10.1177/17588359211059601

Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial. / Ayoub, Jean Pierre; Wildiers, Hans; Friedlander, Michael et al.
I: Therapeutic Advances in Medical Oncology, Bind 13, 12.2021, s. 1-13.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer

T2 - subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial

AU - Ayoub, Jean Pierre

AU - Wildiers, Hans

AU - Friedlander, Michael

AU - Arun, Banu K.

AU - Han, Hyo S.

AU - Puhalla, Shannon

AU - Shparyk, Yaroslav

AU - Jakobsen, Erik H.

AU - Wu, Meijing

AU - Bach, Bruce A.

AU - Feng, Dai

AU - Ratajczak, Christine K.

AU - Maag, David

AU - Diéras, Véronique

PY - 2021/12

Y1 - 2021/12

N2 - Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.

AB - Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.

KW - BRCA

KW - breast cancer

KW - PARP inhibitor

KW - phase 3

KW - TNBC

U2 - 10.1177/17588359211059601

DO - 10.1177/17588359211059601

M3 - Journal article

C2 - 34917174

AN - SCOPUS:85120895655

SN - 1758-8340

VL - 13

SP - 1

EP - 13

JO - Therapeutic Advances in Medical Oncology

JF - Therapeutic Advances in Medical Oncology

ER -

Ayoub JP, Wildiers H, Friedlander M, Arun BK, Han HS, Puhalla S et al. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial. Therapeutic Advances in Medical Oncology. 2021 dec.;13:1-13. doi: 10.1177/17588359211059601