Niraparib Receives FDA Approval for Advanced HDR-Positive Ovarian Cancer

On 23 October 2019, the US Food and Drug Administration (FDA) approved treatment for patients who had received three or more chemotherapy regimens and had advanced, homologous recombination deficiency (HRD)-positive ovarian, fallopian tube or primary peritoneal cancer: niraparib (Zejula).

Homologous recombination deficiency (HRD) was defined as a deleterious or suspected deleterious BRCA mutation or, after the last platinum -based chemotherapy, genomic instability in patients whose disease progressed more than six months after responding.

The Study Leading to Niraparib’s 2nd FDA Approval

In the single-arm QUADRA clinical trial, efficacy was investigated in 98 patients with advanced ovarian cancer and HRD-positive tumors. Patients had previously received three or more lines of chemotherapy. Those previously treated with PARP inhibitors were excluded. For patients without a BRCA mutation, cancer progression at least six months after the last dose of platinum-based treatment was required. HRD-positive status was measured using the Myriad myChoice CDx test: 63 patients had a tumor BRCA mutation (t BRCA m), and 35 had a genomic instability score (GIS) ≥ 42. All patients received 300 mg niraparib once daily until disease progression or unacceptable side effects.

NOTE: Niraparib had previously been approved in 2017 for maintenance treatment of adults with recurrent ovarian, fallopian tube or primary peritoneal cancer whose tumors had completely or partially shrunk with platinum-based chemotherapy, regardless of BRCA mutation status (see). QUADRA’s primary efficacy measures were objective response rate and response duration.

Results

• Among 98 HRD-positive patients, the objective response rate was 24%. All were partial responses.

• Estimated median response duration was 8.3 months.

• In patients positive for BRCA mutations, objective response rates were:

- 39% in the platinum-sensitive group,

- 29% in the platinum-resistant group,

- 19% in the platinum-refractory group.

Side Effects

In QUADRA, 73% of patients receiving niraparib had dose reductions or interruptions. The most common (>5%) side effects leading to dose reduction or interruption were thrombocytopenia (40%), anemia (21%), neutropenia (11%), nausea (13%), vomiting (11%), fatigue (9%) and abdominal pain (5%).

The recommended niraparib doseis 300 mg taken once daily with or without food.

How Does Niraparib Work?

Because cancer cells divide much more frequently and rapidly than normal cells, more DNA damage, or mutations, occurs. When DNA damage occurs, various intracellular mechanisms either repair it or, if it is beyond repair, cause the cell to undergo apoptosis. Both PARP and BRCA play roles in DNA repair. When niraparib, a PARP inhibitor, is used in ovarian cancer, the cancer cell partially loses its ability to repair DNA. If these cells also have a BRCA mutation, their ability to repair their DNA and remain immortal is reduced much further.