Combination of PARP inhibition plus chemotherapy in ovarian cancer

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 phase 3 VELIA trial study, presented by Robert Coleman (University of Texas, MD Anderson Cancer Center, Houston, USA) [1].

The VELIA study evaluated the efficacy of veliparib plus first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in newly diagnosed high grade serous ovarian carcinoma. A total of 1,140 patients were randomised in a 1:1:1 ratio to chemotherapy plus placebo followed by placebo maintenance (Arm 1); chemotherapy plus veliparib followed by placebo maintenance (Arm 2); and chemotherapy plus veliparib followed by veliparib maintenance (Arm 3). Combination chemotherapy was administered for 6 cycles and maintenance therapy was administered for 30 additional cycles. The patients were stratified by stage (III vs IV), residual disease and regimen, region, and germline BRCA status.

The primary endpoint was investigator-assessed progression-free survival (PFS) in Arm 3 compared with Arm 1 using stratification by the presence germline BRCA mutations, and homologous recombination deficiency (HRD; see Figure). Secondary outcomes of overall survival and disease-related symptom scores have yet to be reported.


© Robert L. Coleman (provided by ESMO)

In patients with with BRCA mutations, the median PFS was 34.7 months in Arm 3 compared with 22 months in Arm 1 (HR 0.44; 95% CI 0.28-0.68; P<0.001). In patients with HRD-tumours, the median PFS was 31.9 months vs 20.5 months, respectively (HR 0.57; 95% CI 0.43-0.76; P<0.001). In the intention-to-treat population, the median PFS was 23.5 months in Arm 3 compared with 17.3 months in Arm 1 (HR 0.68; 95% CI 0.56-0.83; P<0.001).

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 high-grade serous carcinoma, 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. The study findings were simultaneously published in the NEJM [2].

Invited discussant Mansoor Raza Mirza (Copenhagen University Hospital, Denmark) said that VELIA demonstrated clinically significant benefit of the experimental arm combining chemotherapy plus veliparib followed by veliparib in maintenance in the population with BRCA mutation or HRD. VELIA is the first phase 3 study to assess impact of combination chemotherapy plus PARPi followed by PARPi. Addition to chemotherapy 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 (in which the PARPi was added as maintenance only). 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.

1. Coleman RL, et al. ESMO Congress 2019. Abstract LBA3.
2. Coleman RL et al. N Engl J Med. 2019 Sep 28.

Posted on 26 November, 201915 February, 2024