The European Commission has approved Lynparza (olaparib), in combination with bevacizumab, as a first-line maintenance therapy for women with advanced ovarian cancer positive for homologous recombination deficiency (HRD) and who responded to platinum-based chemotherapy.

This indication also includes patients with advanced fallopian tube cancer or primary peritoneal cancer. Eligible HRD-positive tumors are those carrying mutations in the BRCA genes, involved in DNA repair, and/or exhibiting genomic instability (a high frequency of mutations within the genome).

The decision comes less than two months after the Committee for Medicinal Products for Human Use, a branch of the European Medicines Agency, issued a positive recommendation, and six months after a similar approval in the U.S.

The combination therapy also is being reviewed by regulatory agencies in Japan and other countries for the same indication.

“For women with advanced ovarian cancer, the goal of 1st-line treatment is to delay disease progression for as long as possible with the intent of achieving long-term remission,” Isabelle Ray-Coquard, MD, PhD, medical oncologist at Centre Léon Bérard, in France, said in a press release. She is also the president of the GINECO group, which specializes in women’s cancers and coordinates clinical trials in France and abroad.

“Unfortunately, once a patient’s cancer recurs, it historically has been incurable,” she added. “Lynparza together with bevacizumab has demonstrated an impressive median progression-free survival benefit of more than three years and is poised to become the standard of care for eligible patients with HRD-positive tumours in the EU.”

Lynparza, an oral treatment developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada), is now approved for three ovarian cancer indications in the EU. The previous approvals include its single use as first-line maintenance therapy for women with BRCA-mutated tumors and as late-line maintenance therapy for those with recurrent cancer, regardless of BRCA mutations.

Since HRD-positive tumors — present in one of every two women with advanced ovarian cancer — rely on other DNA repair mechanisms involving mainly the PARP enzyme, a DNA damage sensor, they are more likely to respond to therapies blocking PARP activity (PARP inhibitors), such as Lynparza.

“Biomarker testing has rapidly enhanced our understanding of how PARP inhibition can help target this disease,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, and chief medical officer at Merck Research Laboratories.

“The EU approval reinforces that HRD-positive tumours represent a distinct subset of advanced ovarian cancer and HRD testing is critical for women in this setting,” he added.

The approval was based on data from a subgroup of women with HRD-positive tumors who participated in the PAOLA-1 Phase 3 study (NCT02477644), of which Ray-Coquard is the principal investigator.

The trial is evaluating whether adding Lynparza to first-line maintenance therapy with bevacizumab (sold as Avastin by Genentech, with biosimilars also available) was superior to bevacizumab alone at delaying disease progression in 806 women with advanced cancer of the ovary, peritoneum, or fallopian tube.

Eligible women had to be at least partially responding to first-line platinum-based chemotherapy. Their tumor HRD status was assessed using Myriad Genetics’ myChoice CDx test — which was approved in the U.S. as a companion diagnostic to identify patients eligible for the Lynparza combo.

Participants were randomly assigned to receive either 300 mg tablets of Lynparza (537 women) or a placebo (269 women), twice daily, for up to two years, in addition to 15 mg/kg of bevacizumab, given directly into the bloodstream every three weeks for 15 months.

PAOLA-1’s main goal was to assess progression-free survival, or the time patients lived without signs of disease progression, while secondary goals included time to second disease progression or death, overall survival, safety, and tolerability.

Top-line results showed that among the 387 women with HRD-positive tumors, the Lynparza-bevacizumab combo significantly lowered the risk of disease progression or death by 67% in those with BRCA mutations, and by 57% in those without BRCA mutations.

Notably, women with BRCA-positive tumors receiving the combination therapy lived about one-and-a-half years longer without signs of disease progression than those given bevacizumab alone (median of 37.2 months vs. 17.7 months). A less pronounced benefit was seen for those without such mutations (median of 28.1 months vs. 16.6 months).

Additional data presented at the 2020 European Society of Medical Oncology virtual congress showed that the combination therapy provided the greatest benefit beyond first disease progression in women with HRD-positive tumors, regardless of tumor BRCA mutation status.

At a median follow-up of three years, the Lynparza-bevacizumab combo significantly lowered the risk of second disease progression or death by 44% in women whose tumors carried BRCA mutations, and by 40% in those without such mutations.

Again, women with BRCA-positive tumors given the combo lived nearly one-and-a-half years longer without signs of second disease progression than those in the bevacizumab group (median of 50.3 vs. 35.3 months).

Notably, these benefits were seen despite the fact that 9% of women in the combination therapy group received a PARP inhibitor after first disease progression, compared with 27% of those in the bevacizumab group.

“Women treated with Lynparza in combination with bevacizumab in the PAOLA-1 Phase 3 trial lived progression-free for a median of more than three years, showing that HRD testing should be an essential component of clinical diagnosis,” said Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit.

“HRD status can help physicians select a personalised 1st-line treatment regimen for patients to substantially delay relapse in this devastating disease,” he added.

To date, the safety profile of the Lynparza-bevacizumab combo was consistent with that previously reported for each medication separately.