Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer

Abstract

Background: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.

Methods: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population.

Results: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.

Conclusions: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

Copyright © 2019 Massachusetts Medical Society.

Figures

Figure 1.. Randomization and Treatment.

Patients were randomly assigned in a 1:1:1 ratio to one of the following three groups: control group (in which patients received chemotherapy plus placebo followed by placebo maintenance); the veliparib-combination-only group (in which patients received chemotherapy plus veliparib followed by placebo maintenance); or the veliparib-throughout group (in which patients received chemotherapy plus veliparib followed by veliparib maintenance). The primary reasons for the discontinuation of veliparib or placebo are shown.

Figure 2.. Kaplan-Meier Estimates of Progression-free Survival in the Veliparib-Throughout Group and Control Group.

Distributions were estimated by means of the Kaplan-Meier method in the intention-to-treat population (Panel A) and in the cohorts of patients with BRCA-mutated tumors or with tumors that had homologous-recombination deficiency (HRD) (Panel B), with the veliparib-throughout group compared with the control group (primary end point). Progression-free survival was compared between the trial-treatment groups by the stratified log-rank test. Hazard ratios were estimated by a Cox model with stratification according to the same factors as were used in the log-rank test. Kaplan-Meier estimates of the percentages of patients who were alive without disease progression at 10 months (approximately 6 months after the completion of chemotherapy) and at 24 months (end of trial-defined therapy) in each population are shown. The dashed line indicates the median, and tick marks indicate censored data.

Figure 3.. Subgroup Analysis of Progression-free Survival.

The hazard ratio in the analysis of progression-free survival is for the comparison of the veliparib-throughout group with the control group. The hazard ratios presented here are from an unstratified Cox proportional-hazards model. Stratification factors included disease stage, paclitaxel regimen, surgery received, and residual disease status after primary surgery. Race was reported by the patient. Eastern Cooperative Oncology Group (ECOG) performance-status scores are assessed on a 5-point scale, with higher scores indicating greater disability. Disease stage was assessed as International Federation of Gynecology and Obstetrics stage III or IV disease. No macroscopic residual disease was defined as either “no residual disease” or “microscopic residual disease only” after surgery, as reported in the electronic data-capture system. Data on BRCA-mutation status were missing for 29 patients in the veliparib-throughout group and for 29 in the control group; data on HRD status were missing for 43 and 44, respectively.