Lynparza (olaparib), in combination with bevacizumab, has been recommended for approval in the European Union (EU) 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.
The positive opinion released by the Committee for Medicinal Products for Human Use (CHMP), an arm of the European Medicines Agency, also includes patients who have advanced fallopian tube or primary peritoneal cancer. CHMP’s recommendations are generally accepted by the European Commission, which makes the final decision on approval.
HRD-positive tumors included in the recommendation are those that carry mutations in the BRCA genes, involved in DNA repair, and/or exhibit genomic instability (a high frequency of mutations within the genome).
Since these tumors rely on DNA repair mechanisms involving mainly the PARP enzyme — a DNA damage sensor — they are more likely to respond to therapies blocking PARP activity, named PARP inhibitors. These include Lynparza, an oral treatment developed by AstraZeneca and Merck (known as MSD outside North America).
“HRD is an important biomarker of advanced ovarian cancer that can inform how physicians in the EU treat this aggressive type of cancer,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a press release.
José Baselga, MD, PhD, executive vice president of AstraZeneca’s oncology research and development, said that “this recommendation is a vital step toward addressing a large and critical unmet need and could bring a new treatment option that significantly delays relapse in this difficult-to-treat disease.”
The committee’s positive opinion follows the combo’s approval in the U.S. for the same indication in May. The combination therapy also is being reviewed by regulatory agencies in Japan and other countries.
If approved, Lynparza will be available in Europe for three indications in ovarian cancer, the previous including 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.
The CHMP’s recommendation was based on data from a subgroup of 387 women with HRD-positive tumors who participated in the PAOLA-1 Phase 3 study (NCT02477644).
The trial evaluated whether adding Lynparza to first-line maintenance therapy bevacizumab (sold as Avastin by Genentech, with biosimilars also available) was superior to bevacizumab alone at delaying disease progression in women with advanced cancer of the ovary, peritoneum, or fallopian tube.
Participants were responding at least partially to first-line platinum-based chemotherapy, and their tumor HRD status was assessed using Myriad Genetics’ myChoice CDx test — which was simultaneously approved in the U.S. as a companion diagnostic to identify patients eligible for the Lynparza combo.
The women were randomly assigned to receive either 300 mg tablets of Lynparza or a placebo, twice daily, for up to two years, in addition to bevacizumab via into-the-vein injections at 15 mg/kg every three weeks for 15 months.
The trial’s main goal was to assess progression-free survival, or the time patients lived without signs of disease progression or until death, while secondary goals included overall survival, safety, and tolerability.
Among 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 carrying mutations in genes other than BRCA, according to top-line results published in The New England Journal of Medicine.
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 treated with bevacizumab alone (median of 37.2 months vs. 17.7 months).
While the combo also significantly prolonged the progression-free survival of women without such mutations, this benefit was less pronounced (median of 28.1 vs. 16.6 months).
“Lynparza together with bevacizumab has demonstrated a median progression-free survival benefit of more than three years vs. 17.7 months with bevacizumab alone, offering new hope for women in this setting,” said Baselga.
Baynes also noted that “this recommendation and the results from the PAOLA-1 trial underscore the importance of HRD testing at diagnosis to determine treatment options for women with advanced ovarian cancer.”
The safety profile of the Lynparza-bevacizumab combo was consistent with that previously reported for each medication separately.
The most common side effects associated with the combo were fatigue, nausea, low red blood cell counts, low number of lymphocytes (a type of white blood cell), vomiting, and low counts of neutrophils (another type of white blood cell).
About half of the women in either group reported severe, life-threatening, or fatal side effects, but a greater proportion of those receiving the combination therapy interrupted treatment due to side effects (54% vs. 24% in the bevacizumab group).
Events associated with the formation of blood clots in the veins carrying blood to the heart also occurred more often in the combo group (5%) than in those treated with bevacizumab alone (1.9%). One woman on the combination therapy died due to simultaneous pneumonia and aplastic anemia.