The U.S. Food and Drug Administration (FDA) has agreed to review AstraZeneca and Merck‘s request to extend the indication of oral Lynparza (olaparib) as a first-line maintenance therapy in combination with bevacizumab for treating women with advanced ovarian cancer who responded to platinum-based chemotherapy, regardless of their BRCA mutation status.
Priority review was granted to the supplemental new drug application for the combo therapy, with a decision expected in the second quarter of this year, according to a press release. This status shortens the agency’s decision to six months, instead of the 10 months typically taken under standard review.
Submission was based on the results of the Phase 3 trial PAOLA-1 (NCT02477644), which compared adding Lynparza to maintenance with bevacizumab (sold as Avastin, with generics also available) versus bevacizumab with a placebo, in women with advanced ovarian cancer, with or without BRCA mutations, who had previously responded to treatment with platinum-based chemotherapy.
Currently, the first-line treatment for women with advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone as maintenance therapy.
During the trial, Lynparza and placebo were given as 300 mg tablets, twice daily, for up to 24 months, and bevacizumab was administered via injections into the vein at 15 mg/kg every three weeks for 15 months.
Trial results showed that women on Lynparza-bevacizumab lived significantly longer without disease progression (22.1 months) than those given bevacizumab alone (16.6 months). There was a 41% reduction in women’s overall risk of disease progression or death with the combination therapy.
The safety and tolerability of adding Lynparza to bevacizumab was consistent with what had been observed 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 cells), vomiting, and joint pain.
PAOLA-1 is the second Phase 3 trial — after SOLO-1 (NCT01844986) — in which findings support the use of Lynparza as a first-line maintenance treatment for patients with advanced ovarian cancer. However, while SOLO-1 showed a benefit of Lynparza in BRCA-mutated cancers only, the combination tested in PAOLA-1 brings benefits to patients with and without BRCA mutations.
In PAOLA-1, the Lynparza-bevacizumab combination reduced the risk of disease progression or death by 69% in women with BRCA mutations, by 67% in those mutations in genes involved in homologous recombination (HR) DNA repair (which also include BRCA genes), and by 57% in those with HR mutations other than in the BRCA genes.
Lynpaza is an oral PARP inhibitor developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada). It acts by blocking the activity of the PARP enzyme, which works as a sensor of DNA damage. By blocking PARP activity, Lynparza leads to the accumulation of DNA damage, which ultimately leads to the death of cancer cells.
It is expected to be particularly effective in cancers with defects in DNA repair pathways — such as those with mutations in BRCA1 and BRCA2 genes — which are more dependent on PARP to survive.
In the event that Lynparza is approved as a maintenance therapy for advanced ovarian cancer, regardless of BRCA status, this would be its fourth indication for ovarian cancer in the U.S.
This year, Lynparza was approved in the U.S., the European Union, and Japan as a first-line maintenance therapy for women with BRCA-positive advanced ovarian cancer, following response to platinum-based chemotherapy.
It also is approved for the treatment of some recurrent or relapsed advanced ovarian cancers, regardless of BRCA status.