2520 - Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer

Background

BRCA-mutated tumors are susceptible to both platinum and PARP inhibitors due to deficiency in homologous recombination repair. Veliparib (Vel) is a PARP1/2 inhibitor with antitumor activity and acceptable toxicity as a single-agent or combined with carboplatin and paclitaxel (C/P) in pts with BRCA mutated breast cancer.

Methods

This double blind, placebo (Pbo)-controlled, phase III trial (NCT02163694) randomized pts 2:1 to C/P with Vel or Pbo. Pts had gBRCA1/2 mutations and ≤2 prior lines of cytotoxic therapy for metastatic breast cancer. Vel (120 mg p.o. BID) or Pbo was given on Days −2 to 5 with C (AUC 6, d1) and weekly P (80 mg/m², d1, 8, 15) in 21-d cycles. Pts who discontinued both C and P but had not progressed received blinded single-agent Vel or Pbo (300-400 mg BID). Treatment was to progression. Primary endpoint was PFS (per investigator); secondary endpoints included OS, clinical benefit rate, objective response rate, and PFS2.

Results

Median age was 47 years (range 24–82), 48% were ER/PgR–, 8% had prior platinum therapy, 4% had history of CNS metastases, and 19% had prior chemotherapy for metastatic disease. Efficacy data are summarized in the Table. Among AEs of special interest (all-grades), neutropenia occurred in 91%/91%, thrombocytopenia in 82%/72%, anaemia in 81%/70%, and nausea and vomiting in 75%/68% of pts in Vel vs Pbo arms, respectively. Most common (≥20%) study drug-related G3+ AEs in Vel and Pbo arms were anaemia (27%/17%), neutropenia (52%/50%), and thrombocytopenia (25%/15%). In Vel vs Pbo arms, 88%/86% had C dose reduction and 74%/70% had P dose reduction.Table:

LBA9

C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; INV, investigator; IRC, independent review committee; m, median; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, time from randomization to progression on first subsequent therapy; DoR, duration of response.

Conclusions

Vel + C/P demonstrated significant improvement in PFS over C/P alone. Median PFS for both arms was over 12 months. Pts on the Vel arm had durable benefit compared to control, with 26% of pts on Vel arm alive and progression-free at 3 years vs. 11% of pts on Pbo arm. Vel did not substantially alter the toxicity profile of C/P.

Clinical trial identification

NCT02163694.

Editorial acknowledgement

Medical writing support was provided by Ana Mrejeru, Ph.D., of AbbVie.

Legal entity responsible for the study

AbbVie.

Funding

AbbVie.

Disclosure

V.C. Diéras: Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Nektar; Advisory / Consultancy: Astellas; Advisory / Consultancy: AbbVie; Advisory / Consultancy: MSD; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Odonate; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: AstraZeneca. H.S. Han: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Prescient; Research grant / Funding (institution): Horizon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): TapImmune; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (self): Department of Defense; Speaker Bureau / Expert testimony: Lilly. B. Kaufman: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Steering committee member : AbbVie; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. H. Wildiers: Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche ; Honoraria (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Amgen; Honoraria (institution): Lilly; Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Vifor Pharma; Honoraria (institution): Celldex Therapeutics; Honoraria (institution): Janssen-CILAG; Honoraria (institution): TRM Oncology; Honoraria (institution): PUMA Biotechnology; Honoraria (institution): ORION corporation. M. Friedlander: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Takeda; Research grant / Funding (self): BeiGene. J. Ayoub: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Roche. S.L. Puhalla: Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Celldex; Advisory / Consultancy: Puma; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: Nanostring; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Covance-Bayer; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Lilly. M. Campone: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy: Accord; Speaker Bureau / Expert testimony: Novartis. M. Jalving: Advisory / Consultancy, Non-remunerated activity/ies, Clinical studies: Merck; Advisory / Consultancy, Non-remunerated activity/ies, Clinical studies: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Tesaro; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Non-remunerated activity/ies, Clinical studies: Cristal Therapeutics; Non-remunerated activity/ies, Clinical studies: AbbVie. C. Oprean: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sandoz; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Roche; Speaker Bureau / Expert testimony: Teva; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: BMS; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Janssen; Non-remunerated activity/ies, Research /Clinical studies: AbbVie; Non-remunerated activity/ies, Research /Clinical studies: Genentech; Non-remunerated activity/ies, Research /Clinical studies: BeiGene; Non-remunerated activity/ies, Research /Clinical studies: Trio Oncology. M. Palácová: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Eisai. Y.H. Park: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Merck; Research grant / Funding (self): Roche. Y. Shparyk: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Roche; Speaker Bureau / Expert testimony: AstraZeneca; Non-remunerated activity/ies, Research /Clinical studies: MSD; Non-remunerated activity/ies, Research /Clinical studies: Boehringer Ingelheim; Non-remunerated activity/ies, Research /Clinical studies: AbbVie. M. Dudley: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. C.K. Ratajczak: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. D. Maag: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. B.K. Arun: Research grant / Funding (self), Non-remunerated activity/ies, Steering Committee: AbbVie; Research grant / Funding (self): PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Invite. All other authors have declared no conflicts of interest.