Veliparib regimen boosts PFS in women with advanced ovarian cancer

Veliparib added onto frontline chemotherapy followed by veliparib maintenance monotherapy(veliparib throughout) significantly prolonged progression-free survival (PFS) in women with newly diagnosed high-grade serous ovarian carcinoma, the phase III placebo-controlled VELIA/GOG-3005 trial has shown.

Women treated with veliparib throughout achieved a significantly longer median PFS than women treated with chemotherapy alone (control group). “The benefit was observed in the full cohort regardless of BRCA mutation or homologies recombination deficiency (HRD) status,” said study author Dr Robert Coleman from the MD Anderson Cancer Centre in Houston, Texas, US. [ESMO 2019, abstract LBA3; N Engl J Med 2019;doi:10.1056/NEJMoa1909707)

In the intention-to-treat population, median PFS was 23.5 months with veliparib throughout vs 17.3 months for chemotherapy alone (hazard ratio [HR], 0.68, 95 percent confidence interval [CI], 0.56–0.83; p<0.001).

PARP* inhibitor added to chemo in VELIA

Veliparib, a PARP inhibitor, has demonstrated single-agent activity in recurrent germline BRCA1- or BRCA2-positive ovarian cancer. There have been interests in combining PARP inhibitors with cytotoxic chemotherapy for ovarian cancer treatment, but those efforts have been limited by unacceptable haematologic toxicity that often requires substantial dose reductions, said Coleman.

VELIA is the first phase III study to assess the impact of combination chemotherapy plus a PARP inhibitor. The study involved 1,140 women with previously untreated stage III or IV high-grade serous epithelial ovarian cancer, all of whom received first-line induction chemotherapy with carboplatin and paclitaxel. They had ECOG performance status 0–2, without  central nervous system metastases. Germline and tissue BRCA mutations and HRD were determined by central testing. Twenty-six percent of the patients had BRCA mutations and 55 percent  had HRD.

Patients were randomized to one of three groups: veliparib 150 mg twice daily added onto chemotherapy followed by veliparib 400 mg twice daily for 30 cycles as maintenance (veliparib-throughout, n=382), veliparib + chemotherapy followed by placebo for maintenance (veliparib combination only, n=383), or chemotherapy alone (control, n=375).

There was a significant benefit with veliparib-throughout regimen, but the independent value of adding veliparib to chemotherapy without veliparib maintenance was less clear, Coleman reported. Veliparib plus chemotherapy also led to a higher incidence of anaemia and thrombocytopenia, as well as nausea and fatigue, overall. But Coleman said the toxicities observed with veliparib were consistent with the known safety profile of veliparib.

Certain subgroups of patients derived greater benefits. To illustrate this point, median PFS in women with BRCA mutation was 34.7 months in the veliparib-throughout group vs 22 months in the control group (HR for progression or death, 0.44, 95 percent CI, 0.28–0.68; p<0.001). In patients with HRD, PFS was 31.9 and 20.5 months, respectively (HR 0.57, 95 CI, 0.43–0.76; p<0.001).

A new standard of care for newly diagnosed ovarian cancer?

The data regarding overall survival were not sufficiently mature in the BRCA-mutation cohort, the HRD cohort, and the ITT population, with percentages of required endpoints of 21 percent, 24 percent, and 49 percent, respectively. And because of the testing hierarchy, OS in the veliparib-throughout group vs the control group cannot be tested until a sufficient number of events have occurred, so formal hypothesis testing of PFS in the veliparib combination-only group vs the control group has not been performed, said Coleman.

“Still, we believe veliparib in combination with chemotherapy, and continued as maintenance, should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer,” Coleman concluded.

“The time has come for all patients to have a PARP inhibitor,” said discussant Dr Mansoor Raza Mirza from the Rigshospitalet of Copenhagen University in Copenhagen, Denmark.