As first-line treatment for women with advanced ovarian cancer, the addition of veliparib during induction followed by veliparib maintenance therapy significantly reduced the risk of disease progression or death in the phase III VELIA/GOG-3005 trial reported at the European Society for Medical Oncology (ESMO) Congress 2019 by Robert L. Coleman, MD, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, Houston.¹ The results were simultaneously published in The New England Journal of Medicine.²

“Veliparib in combination with chemotherapy should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer.”

— Robert L. Coleman, MD

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Data are limited regarding the use of poly (ADP-ribose) polymerase (PARP) inhibitors such as veliparib, in combination with chemotherapy and followed by maintenance, as initial treatment in patients with ovarian cancer. Veliparib is characterized by strong catalytic effects on PARP but a relatively low degree of PARP trapping, and as such has been successfully combined with several cytotoxic agents, including paclitaxel and carboplatin.

VELIA evaluated the benefit of such a regimen in 1,140 women newly diagnosed with stage III or IV high-grade serous ovarian carcinoma, enrolled at 202 sites in 20 countries.

“The reduction in the hazard for disease recurrence or progression was 56% in patients with BRCA mutations, 43% in patients with homologous recombination deficiency, and 32% in the intent-to-treat population,” said Dr. Coleman. “Veliparib in combination with chemotherapy should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer.”

VELIA/GOG-3005

Germline or somatic BRCA status was determined for all 1,140 patients, as was homologous recombination deficiency status by the Myriad myChoice HRD CDx assay. Approximately 30% of the cohort harbored BRCA1 or BRCA2 mutations; 63% were homologous recombination deficiency–positive (which included the BRCA-mutated cohort), and 37% were homologous recombination deficiency–negative (ie, homologous recombination proficient). For 78 patients, homologous recombination deficiency status was unknown.

Cytoreductive surgery could be performed before starting or after three cycles of treatment. Of note, approximately two-thirds of patients undergoing primary cytoreduction achieved a complete gross resection; a similar rate of complete gross resection was achieved following neoadjuvant chemotherapy.

The patients were randomly assigned 1:1 to one of three treatment arms:

• Veliparib-throughout group (n = 383): Induction with veliparib plus carboplatin and paclitaxel, followed by veliparib maintenance
• Veliparib combination–only group (n = 383): Induction with veliparib plus carboplatin and paclitaxel followed by placebo maintenance
• Control group (n = 375): Induction with carboplatin and paclitaxel followed by placebo maintenance.

Oral veliparib was administered at 150 mg twice daily during induction; the maintenance dose was 300 mg twice daily for 2 weeks, then escalating to 400 mg twice daily if tolerated. Carboplatin was administered at AUC 6 every 3 weeks, and paclitaxel was administered at 175 mg/m² every 3 weeks or at 80 mg/m² weekly. Combination chemotherapy was given for 6 cycles, and maintenance therapy was given for 30 additional cycles.

The primary endpoint was investigator-assessed progression-free survival in the veliparib-throughout group vs control group, analyzed sequentially for the BRCA-mutation cohort, the homologous recombination deficiency–positive cohort, and the intent-to-treat population.

Primary Endpoint Met

Patients who received veliparib-throughout treatment had a significantly improved progression-free survival, with the effect most pronounced in homologous recombination deficiency–positive patients. At a median follow-up of 28 months, median progression-free survival was 23.5 months in the overall veliparib-throughout group and 17.3 months in the control group (hazard ratio [HR] = 0.68; P < .001). This benefit rose to 34.7 months vs 22.0 months (HR = 0.44; P < .001) for the cohort with BRCA mutations (n = 200) and to 31.9 months vs 20.5 months (HR = 0.57; P < .001) for the homologous recombination deficiency–positive cohort (n = 421), Dr. Coleman reported.

“Analysis of progression-free survival in predefined subgroups was directionally consistent and aligned with the primary analysis in the intent-to-treat population. Similarly, detailed subgroup analyses in the BRCA-mutation cohort demonstrated a consistent and robust effect,” he added.

The investigators conducted several hypothesis-generating exploratory analyses in a series of subcohorts. Noting that these analyses are underpowered and unstratified, they reported modest reductions in risk for veliparib-throughout vs control in the true BRCA wild-type population (HR = 0.81), the homologous recombination deficiency–positive/BRCA wild-type population (HR = 0.74), and the non–homologous recombination–deficient/BRCA wild-type population (HR = 0.80).

A full analysis of the veliparib combination–only arm (which lacked veliparib maintenance) was not reported, but Dr. Coleman noted that the outcomes in this cohort were not significantly better than those in the control arm. Nevertheless, numerically higher response rates were observed in both veliparib-containing arms, he said.

Safety Profile

“Adverse events with veliparib were consistent with chemotherapy during the combination phase and consistent with the veliparib safety profile during maintenance,” Dr. Coleman reported.

Toxicity rates were similar between the veliparib-throughout group and the control group; however, thrombocytopenia occurred more often with veliparib, in approximately 60% of patients vs 30% of controls. The most common adverse event on the veliparib arm was nausea (80%), but almost all cases were mild. One case of myelodysplastic syndrome and one case of acute myeloid leukemia were reported in patients taking veliparib.

In the combination chemotherapy phase, 11% or fewer patients had an adverse event leading to the discontinuation of veliparib or placebo in any group. In the maintenance phase, discontinuation rates were 19% with veliparib (mostly due to nausea) and 6% with placebo.

In health-related quality-of-life assessments, the mean change from baseline increased over time, indicating improvement, particularly after chemotherapy was completed. Differences in these changes between treatment groups were small and not considered clinically significant.

“Veliparib added to chemotherapy and continued as maintenance significantly extended progression-free survival in all patient cohorts with newly diagnosed high-grade serous ovarian carcinoma regardless of biomarker, choice of surgery, or paclitaxel regimen,” Dr. Coleman said. “We believe these data support veliparib administered during chemotherapy and continued as maintenance as a new standard of care.” 

DISCLOSURE: The VELIA trial was funded by AbbVie. Dr. Coleman has consulted or advised for Clovis Oncology, Genentech/Roche, Esperance, National Comprehensive Cancer Network, AstraZeneca/MedImmune, Genmab, GamaMabs Pharma, Tesaro, OncoMed, Sotio, Oncolytics, and AbbVie and has received travel funding from Merck, Astra/Zeneca/MedImmune, Array Biopharma, Clovis, Roche/Genentech, Research to Practice, GOG, Sotio, and the Vaniam Group.

REFERENCES

1. Coleman RL, Fleming GF, Brady MF, et al: VELIA/GOG-3005: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin. ESMO Congress 2019. Abstract LBA3. Presented September 28, 2019.

2. Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. September 28, 2019 (early release online).