Patients with high-grade serous ovarian cancer experienced a 32% reduction in the risk of progression or death with frontline combination veliparib plus carboplatin and paclitaxel followed by veliparib maintenance, according to the data from the phase III VELIA trial presented at the 2019 ESMO Congress, and simultaneously published in the New England Journal of Medicine.
Robert Coleman, MD
Patients with high-grade serous ovarian cancer experienced a 32% reduction in the risk of progression or death with frontline combination veliparib plus carboplatin and paclitaxel followed by veliparib maintenance, according to data from the phase III VELIA trial presented at the 2019 ESMO Congress, and simultaneously published in theNew England Journal of Medicine(NEJM).1,2
Across all patient subgroups, the median progression-free survival (PFS) for the induction and maintenance phases combined in the veliparib arm was 23.5 months compared with 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83;P<.001). The benefit was more pronounced for those withBRCAmutations. In this group, the median PFS was 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28-0.68;P<.001).
Another arm explored frontline veliparib plus chemotherapy followed by placebo maintenance; however, a benefit for veliparib was not demonstrated in this arm of the trial compared with chemotherapy plus placebo with placebo maintenance. Findings for this group were published inNEJMbut not presented in full at the ESMO Congress.
"Veliparib added to chemotherapy and continued as maintenance significantly extended PFS in all patient cohorts with newly diagnosed high-grade serous ovarian carcinoma, regardless of biomarker, choice of surgery, or paclitaxel regimen," said lead author Robert L. Coleman, from the University of Texas MD Anderson Cancer Center. "Veliparib in combination with chemotherapy should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer."
The VELIA study randomized patients evenly between 3 arms: the first arm (control) consisted of carboplatin and paclitaxel with placebo followed by placebo as maintenance (n = 375). The second arm of the study examined the addition of veliparib at 150 mg twice daily to carboplatin and paclitaxel as induction therapy followed by placebo maintenance (n = 383). In the third arm, veliparib was added at 150 mg twice daily to carboplatin and paclitaxel followed by veliparib alone at 400 mg twice daily as maintenance (n = 382).
Patient characteristics were well balanced across arms. The median age of patients was 62 years, and approximately 60% had an ECOG performance status of 0. Two-thirds of patients had stage III disease, and most had received primary surgery, with the remaining having interval surgery. Nearly half of patients in both groups had no residual disease, and approximately 30% had residual disease.
In those testing positive for homologous recombination deficiency (HRD), the median PFS was 31.9 months in those receiving veliparib throughout the trial compared with 20.5 months in the control arm (HR, 0.57; 95% CI, 0.43-0.76;P<.001). Data were not yet sufficiently mature to conduct overall survival analyses across the groups.
In those receiving veliparib with induction chemotherapy followed by placebo maintenance, the median PFS across the full study was 15.2 months compared with 17.3 months in the control arm (HR, 1.07; 95% CI, 0.90-1.29). In theBRCAgroup, the median PFS was 21.1 months with this regimen compared with 22.0 months for the control (HR, 1.22; 95% CI, 0.82-1.80). In the HRD-positive group, the median PFS was 18.1 months with the combination compared with 20.5 months for the control (HR, 1.10; 95% CI, 0.86-1.41).
An objective response rate (ORR) was available for patients with measurable disease at study entry (25% of study). Those receiving veliparib throughout the full study had an ORR of 84% compared with 79% and 74% in the veliparib upfront alone and control arms, respectively.
An assessment of PFS prior to beginning maintenance therapy revealed some data on the efficacy of adding veliparib to the frontline therapy. In this analysis, PFS was not improved with the combination of veliparib and chemotherapy versus the control group (HR, 1.07; 95% CI, 0.90-1.29). These findings were consistent across subgroups.
At least one treatment-emergent adverse event (AE) was experienced by all patients across the 3 arms. Grade 3/4 AEs were experienced by 88% of those receiving veliparib throughout and for 88% of those receiving veliparib only in the induction combination. In the control arm, grade 3/4 AEs were experienced by 77% of patients.
The most commonly observed grade 3/4 AEs in the veliparib throughout group compared with control, respectively, were neutropenia (58% vs 49%), anemia (38% vs 26%), thrombocytopenia (28% vs 8%), and leukopenia (18% vs 9%). In the veliparib induction/placebo maintenance group, the most common grade 3/4 AEs were neutropenia (62%), anemia (41%), thrombocytopenia (31%), and leukopenia (12%).
"Veliparib could be safely administered with carboplatin and paclitaxel," said Coleman. "Adverse events with veliparib were consistent with chemotherapy during combination phase and consistent with veliparib safety profile during maintenance phase."
VELIA Trial Draws Criticism
Commenting on the data, ESMO expert Mansoor Raza Mirza, MD, noted that a fourth arm looking at induction chemotherapy plus placebo followed by maintenance veliparib would have helped make data from the study more definitive, as it was hard to ascertain whether the benefit was primarily derived from the induction or maintenance therapy. While Mirza did note that VELIA was the first phase III study to assess the impact of chemotherapy plus a PARP inhibitor, he described several critiques concerning this approach.
"The addition caused increased toxicity, reduced use of potentially curative chemotherapy, and did not provide a benefit over what is observed in other PARP first-line trials," Mirza said. "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."