Update on PARP Inhibitors for Ovarian Cancer with BRCA Mutations

Each year in the United States, roughly 22,000 women are diagnosed with ovarian cancer and more than 15,000 die of the disease. Treatment for ovarian cancer commonly involves surgery and/or chemotherapy. Researchers continue to study new approaches for improving the outcomes of all women affected by ovarian cancer but progress has been slow.

The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Drugs that inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy. PARP inhibitors are thought to have the greatest effect in women with mutations of the BRCA genes, who represent about 15% of ovarian-cancer patients. But recent research, still ongoing, indicates that the drugs may benefit an additional 35% of patients with different genetic profiles.

One PARP inhibitor pill is already available Lynparza, but it is approved for only a small share of patients. Two other drugs in the class; rucaparib and niraparib could be approved as soon as next year for many more patients following the release of encouraging clinical trial data this summer.

LynparzaTM (olaparib) constitutes the first PARP inhibitor approved for treating ovarian cancer. Lynparza was approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment.1

The FDA approved Lynparza with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10 to 15 percent of all ovarian cancer is associated with these hereditary BRCA mutations.

Lynparza was evaluated in a study where 137 participants with gBRCAm-associated ovarian cancer received the drug. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed that 34% of participants experienced an ORR for an average of 7.9 months.

Rucaparib was evaluated in 35 patients (ages 44–84) with BRCA-positive ovarian cancer that had returned after previous treatment. Participants had received between two and four prior chemotherapy regimens and had experienced a progression-free survival interval of six months or more. Patients were given 600 mg of rucaparib daily in 21-day cycles until ovarian cancer progressed. Overall more than half of the patients responded to treatment with rucaparib, which had an overall response rate of 65%. Patients who had the longest time to cancer progression before the study had the highest response rates.2

Niraparib also appears to improve the time to cancer progression among patients with recurrent ovarian cancer when used as maintenance therapy during platinum-based chemotherapy. Although patients often respond to initial therapy that includes platinum-based chemotherapy, approximately 90% of patients will experience a progression of their cancer within 2 years of their initial therapy.

Researchers recently conducted a phase III trial referred to as the NOVA trial, to determine the effectiveness of niraparib in the treatment of recurrent ovarian cancer. The trial included approximately 500 women who had responded to platinum-based chemotherapy for recurrent ovarian cancer. One group of patients received niraparib following chemotherapy, while the other received placebo (inactive substitute) until their cancer started progressing.3

One group of patients in the trial had a BRCA1 or BRCA2 germline gene mutation, which predisposes individuals to a significantly increased risk of developing ovarian cancer within their lifetime; one group of patients had homologous recombination deficiency (HRD) without germline BRCA1 or BRCA2 mutations; and one group of individuals had neither BRCA1 or BRCA2 germline mutations nor HRD.

  • Among patients with germline BRCA1 or 2 mutations, median survival time without progression of cancer (progression-free survival, PFS) was 21 months among patients treated with niraparib, compared with only 5.5 months for those who received placebo.
  • Among patients without germline BRCA1 or 2 mutations who were HRD-positive, the median PFS was 12.9 months for those treated with naraparib, compared with only 3.8 months for those who received placebo.
  • Among patients without germline BRCA1 or 2 mutations who had either HRD-positive or HRD-negative cancers, median PFS was 9.3 months for those treated with naraparib, compared with 3.9 months for who received placebo.
  • The most common serious side effects associated with niraparib were low blood cell levels.

Niraparib appears to significantly improve PFS when used as maintenance therapy among patients with recurrent ovarian cancer who respond to platinum-based chemotherapy. Patients with BRCA1 and BRCA2 germline mutations appear to derive the greatest benefit from niraparib; however, all patients in the NOVA trial experienced an improved PFS from treatment with niraparib. Filing for approval of niraparib is expected later this year.

Reference:

  1. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm427554.htm
  2. Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Journal of Clinical Oncology. 33, 2015 (supplement; abstract 5513).
  3. Tesaro Inc., press release. Tesaro’s niraparib significantly improved progression-free survival for patients with ovarian cancer in both cohorts of the phase 3 NOVA trial. Available at: http://ir.tesarobio.com/releasedetail.cfm?ReleaseID=977524. Accessed July 6, 2016.

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