FDA Approves Lynparza Combo as First-line Maintenance Therapy for Advanced Ovarian Cancer

FDA Approves Lynparza Combo as First-line Maintenance Therapy for Advanced Ovarian Cancer

The U.S. Food and Drug Administration (FDA) 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 who have advanced fallopian tube or primary peritoneal cancer.

HRD-positive tumors — present in one of every two women with advanced ovarian cancer — have mutations in certain genes involved in DNA repair, including the BRCA genes, and/or genomic instability (a high frequency of mutations within the genome).

Since these tumors rely on other DNA repair mechanisms mainly involving the PARP enzyme — a DNA damage sensor — they are more likely to respond to therapies blocking PARP activity (PARP inhibitors), such as Lynparza.

Patients’ eligibility for this combination therapy will be evaluated using the Myriad myChoice CDx test, which was simultaneously approved by the FDA as a companion diagnostic to identify these DNA repair defects in tumors.

This is now the fourth FDA-approved indication for Lynparza, an oral treatment developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada). The previous three approvals include first-line maintenance therapy and late-line treatment for women with BRCA-mutated advanced ovarian cancer, as well as late-line maintenance therapy for those with recurrent ovarian cancer, regardless of BRCA mutations.

“This approval represents another milestone for Lynparza in patients with ovarian cancer,” Dave Fredrickson, AstraZeneca’s executive vice president and head of the oncology business unit, said in a press release.

The combination therapy also is being reviewed for the same indication in the European Union, Japan, and other countries.

The FDA’s decision was based on data from a subgroup of 387 women with HRD-positive tumors who participated in the Phase 3 PAOLA-1 study (NCT02477644).

PAOLA-1 evaluated whether adding Lynparza to first-line maintenance therapy bevacizumab (sold as Avastin by Genentech, with biosimilars also available) was superior to bevacizumab alone in women newly-diagnosed with advanced cancer of the ovary, peritoneum, or fallopian tube, regardless of BRCA mutations.

These women had responded at least partially to first-line platinum-based chemotherapy. HRD status was assessed with the myChoice CDx test.

Participants were assigned randomly to receive 300 mg tablets of Lynparza or a placebo, twice daily, for up to two years, in addition to bevacizumab via injections into the bloodstream at 15 mg/kg every three weeks for 15 months.

The trial’s main goal was to assess progression-free survival (PFS), or the time a patient lives without disease progression or death. Secondary goals included overall survival, safety, and tolerability.

Results from the HRD-positive subgroup of women showed that adding Lynparza to bevacizumab significantly lowered the risk of disease progression or death by 67% in women with BRCA mutations and by 57% in women with mutations other than in the BRCA genes.

Notably, women receiving the Lynparza-bevacizumab combo lived significantly longer without signs of disease progression than those treated with bevacizumab alone — a median of 28.1 vs. 16.6 months in those without BRCA mutations, and 37.2 months vs. 17.7 months in those with BRCA mutations.

“The median progression-free survival of more than three years offers new hope for more women to delay relapse in this difficult-to-treat disease,” said Fredrickson. “These results further establish that HRD-positive is a distinct subset of ovarian cancer, and HRD testing is now a critical component for the diagnosis and tailoring of treatment for women with advanced ovarian cancer.”

Adding Lynparza to bevacizumab showed similar safety and tolerability to those reported for each medication separately in prior studies.

The most common side effects associated with the combo were fatigue, nausea, high blood pressure, low red blood cell counts, low number of lymphocytes (a type of white blood cell), vomiting, and joint pain.

Severe, life-threatening or fatal side effects were reported in 57% of women receiving the combination therapy and in 51% of those on bevacizumab alone.

Side effects leading to treatment interruption occurred more often in the combination therapy group than in the bevacizumab group (54% vs. 24%). The same was true for events associated with the formation of blood clots in the veins carrying blood to the heart (5% vs. 1.9% in those treated with bevacizumab alone). One woman on Lynparza died due to concurrent pneumonia and aplastic anemia.

“Advances in understanding the role of biomarkers and PARP inhibition have fundamentally changed how physicians treat this aggressive type of cancer,” said Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories.

Isabelle Ray-Coquard, MD, PAOLA-1’s principal investigator and medical oncologist at Centre Léon Bérard, in France, added: “The combination of Lynparza and bevacizumab now provides women with HRD-positive advanced ovarian cancer with a new standard of care and I look forward to seeing this translate into clinical practice.”