H S Han1, V Diéras2, M Robson3, M Palácová4, P K Marcom5, A Jager6, I Bondarenko7, D Citrin8, M Campone9, M L Telli10, S M Domchek11, M Friedlander12, B Kaufman13, J E Garber14, Y Shparyk15, E Chmielowska16, E H Jakobsen17, V Kaklamani18, W Gradishar19, C K Ratajczak20, C Nickner20, Q Qin20, J Qian20, S P Shepherd20, S J Isakoff21, S Puhalla22. 1. Moffitt Cancer Center, Tampa, USA. 2. Institut Curie, Paris, France, USA. 3. Weill Cornell Medical College, New York, USA. 4. Masarykuv Onkologický Ústav, Brno, Czech Republic, Durham, USA. 5. Duke University, Durham, USA. 6. Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 7. Dnepropetrovsk Medical Academy, City Hospital #4, Dnipro, Ukraine. 8. Midwestern Regional Medical Center, Zion, USA. 9. Institut de Cancérologie de l'Ouest, Saint Herblain, France. 10. Stanford University School of Medicine, Stanford, USA. 11. University of Pennsylvania, Philadelphia, USA. 12. Prince of Wales Hospital, Sydney, Australia. 13. Sheba Medical Center, Tel Hashomer, Israel. 14. Dana-Farber Cancer Institute, Boston, USA. 15. Chemotherapy Department, Lviv State Regional Treatment and Diagnostics Oncology Center, Lviv, Ukraine. 16. Department of Clinical Oncology, Oncology Centre, Bydgoszcz, UMK, Torun, Poland. 17. Department of Oncology, Vejle Hospital/Lillebaelt Hospital, Vejle, Denmark. 18. Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, USA. 19. Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA. 20. AbbVie Inc., North Chicago, USA. 21. Massachusetts General Hospital, Boston, USA. 22. University of Pittsburgh Cancer Institute, Pittsburgh, USA.
Abstract
Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receivingVCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.
RCT Entities:
Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.
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