A regimen of veliparib integrated into standard front-line treatment with carboplatin plus paclitaxel with continued veliparib maintenance significantly improved progression-free survival (PFS) in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC), investigators reported at the ESMO Congress 2019 in Barcelona, Spain.
Robert L. Coleman, Department of Gynecologic Oncology and Reproductive Medicine, The MD Anderson Cancer Centre in Houston, United States of America reported the results from the phase III randomised, placebo-controlled, multinational VELIA/GOG-3005trial (NCT02470585). The study investigated whether PFS could be increased by adding veliparib to front-line carboplatin and paclitaxel and continuing veliparib as maintenance therapy in patients with newly diagnosed HGSC with and without germline BRCA mutations, and homologous recombination deficiency (HRD).
The study randomly assigned 1140 previously untreated patients with stage III-IV HGSC to one of 3 cohorts: patients in arm 1 received carboplatin/paclitaxel plus placebo followed by placebo maintenance, patients in arm 2 received carboplatin/paclitaxel plus veliparib followed by placebo maintenance, and patients in arm 3 received carboplatin/paclitaxel plus veliparib followed by veliparib maintenance. Oral veliparib was administered during carboplatin/paclitaxel cycles at 150 mg twice daily and and at 400 mg twice daily for 30 cycles as maintenance. The patients were stratified by stage (III versus IV), residual disease and regimen, region, and germline BRCA status.
The primary endpoints were PFS per Kaplan-Meier comparison of arm 3 versus arm 1 using hierarchical testing in patients according to stratification and in the entire patient population by log-rank tests. Secondary endpoints included PFS in arm 2 versus arm 1, overall survival (OS), and disease related symptom scores. Germline and tissue BRCA mutations and HRD were determined by central testing; 26% of patients had BRCA mutation and 55% had HRD. The results presented at ESMO 2019 Congress compared PFS in arm 3 with arm 1, in support of the VELIA/GOG-3005 trial’s primary endpoint.
The study primary endpoint was met
The comparison of data from 382 patients in arm 3 receiving veliparib plus chemotherapy with veliparib maintenance to 375 patients in arm 1 receiving placebo plus chemotherapy with placebo maintenance showed median PFS was 23.5 months in arm 3 versus 17.3 months in arm 1 (hazard ratio [HR] 0.68; 95% confidence interval [CI], 0.56-0.83; p < 0.001).
Patients with HGSC and BRCA mutation or HRD also achieved significantly improved PFS with the veliparib regimen
Comparison of arms 3 and 1 in patients with BRCA mutation revealed that 108 patients in arm 3 had median PFS of 34.7 months versus 22.0 months in 92 patients in arm 1 (HR 0.44; 95% CI, 0.28, 0.68; p < 0.001). A similar comparison in patients with HRD showed patients receiving veliparib/chemotherapy followed by veliparib achieved median PFS of 31.9 months versus 17.3 months in patients on the placebo/chemotherapy regimen (HR 0.57; 95% CI, 0.43, 0.76; p < 0.001).
PFS for primary endpoint (PFS) in the 3 analytical cohorts. Arm 3 (Veliparib-throughout) vs Arm 1 (control).
© Robert L. Coleman.
The relative carboplatin and paclitaxel dose intensities were similar between arms.
The safety analysis of patients in arm 3 versus arm 1 showed that more patients receiving additional veliparib during the chemotherapy phase experienced grade 3-4 adverse events (AEs) of thrombocytopenia (27% versus 8%). During the maintenance phase of veliparib versus placebo, more patients had any grade 3-4 AEs with veliparib (45% versus 32%). However, the incidence of serious AEs was similar (17% versus 19%).
Discussant points
Mansoor Raza Mirza of the Rigshospitalet (Copenhagen University Hospital), Copenhagen, Denmark who discussed the study findings said that VELIA demonstrated clinically significant benefit of chemotherapy plus veliparib followed by veliparib in maintenance in the population with BRCA mutation. VELIA is the first phase III study to assess impact of combination chemotherapy plus PARPi > PARPi. Addition caused increased toxicity, reduced use of potentially curative chemotherapy and did not provide a benefit over what is observed in other PARPi first-line trials. Absence of comparator arm with veliparib in maintenance phase only makes it unclear if addition of veliparib to chemotherapy is necessary to provide observed benefit.
Conclusions
The investigators concluded that the addition of veliparib to front-line carboplatin and paclitaxel with continued veliparib monotherapy maintenance significantly improved PFS in all cohorts of women with newly diagnosed HGSC, including the overall population without selection for biomarkers, nor timing or outcome of cytoreductive surgery and in cohorts of patients with BRCA mutation or HRD. They further concluded that the improved PFS was irrespective of the response to carboplatin/paclitaxel. Toxicities observed with veliparib were consistent with the known veliparib safety profile.
The study findings are simultaneously published in the NEJM.
Disclosure
This study was funded by AbbVie.
References
LBA3 – Coleman RL, Fleming GF, Brady MF, et al. VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC).
Coleman RL, Fleming GF, Brady MF, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med; Advance online publication 28 September 2019. DOI: 10.1056/NEJMoa1909707