Significant developments in ovarian cancer signal changes in disease management

Ovarian cancer is one of the main causes of death from gynecological cancers worldwide. Advanced disease is usually treated with platinum and taxane treatment, resulting in relatively good responses in the first-line setting. Most patients, however, experience relapse and although some can be re-challenged with platinum-based therapies (typically with poor effectiveness), patients with platinum-resistant disease have very few treatment options.

A series of presentations at ESMO 2016 have highlighted significant, potentially practice-changing developments in the treatment of ovarian cancer. During Saturday’s Presidential Symposium, Dr. Mansoor Mirza presented data from the ENGOT-OV16/NOVA Phase III trial in which Tesaro’s niraparib as maintenance treatment improved the outcome of platinum-sensitive, recurrent ovarian cancer patients. The PARP inhibitor significantly improved PFS (vs. placebo) in patients with germline BRCA mutations (gBRCAm)—21 months vs. 5.5 months.

As PARP proteins have a role in DNA repair, and BRCA genes encode for PARP-independent DNA repair enzymes, BRCA mutation-positive tumors are particularly responsive to PARP inhibitors. Only a small proportion (around 10%)of ovarian cancer patients however, harbor BRCA mutations. Lynparza, AstraZeneca’s Lynparza, was the first PARP inhibitor to be approved for the treatment of previously-treated ovarian cancer with BRCA mutations. In contrast to the clinical development of Lynparza, which focused on BRCA-mutated patients, the NOVA study investigated niraparib in patients with high-grade serous histology and platinum sensitivity or patients with gBRCA mutations. Notably, niraparib also improved the PFS of patients who did not carry BRCA mutations or other homologous recombination DNA-repair deficiencies (9.3 months vs. 3.9 months for placebo) in the NOVA trial. This would open the market for this PARP inhibitor beyond the BRCA-mutated ovarian cancer patients, as there are no targeted therapies available for high-grade serous ovarian cancer.

Lynparza’s European label includes its use as maintenance therapy in platinum-sensitive, BRCA-mutation-positive (germline or somatic), high-grade serous ovarian cancer. Niraparib’s results from the NOVA trial are seen as a welcome breakthrough, as the PARP inhibitor could now be used in a much larger patient population than that targeted by Lynparza. The drug has a manageable side effect profile, and although grade 3/4 hematological toxicities were common, they did not lead to a high number of discontinuations in the NOVA trial.

With trials like ARIEL-2 (Clovis Oncology’s rucaparib), Study-19 (Lynparza), and now NOVA strengthening the position of PARP inhibitors within the ovarian cancer treatment algorithm, in Sunday’s “BRCA testing to drive treatment in ovarian cancer” session, Dr. Pujade-Lauraine highlighted the need for a change in how BRCA testing is performed. Currently, patients are referred to genetic counseling for germline BRCA (gBRCA) testing, as the results not only impact the patient, but also their family. After counselling, patients can opt to have the test or not, thus making genetic counseling a major limiting factor in the testing all ovarian cancer patients. Indeed, a recent paper collating data from 22 collaborative groups from 19 countries showed that BRCA testing is carried out almost exclusively in patients with ovarian and breast cancer family history and/or histology.

Dr. Pujade-Lauraine’s elegant proposal outlines that all patients should be informed and tested for somatic BRCA-mutations. Then, if positive for a somatic BRCA mutation, patients would receive further genetic counseling and have the option to undergo gBRCA testing as well. It remains unclear whether reimbursement issues will prevent all ovarian patients from undergoing BRCA testing, especially in the more cost-constrained Europe countries; and although therapies such as niraparib can offer significant benefit to ovarian cancer patients regardless of their BRCA mutational status, the solution proposed would signal a step forward in the era of personalized medicine in ovarian cancer.

References:

  1. Mirza AR, et al. New England Journal of Medicine 2016, October 07.
  2. Lheureux S, et al. Gynecologic Oncology 2016; 140(1):90-94.

 

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