Promise of PARP Inhibitors for BRCA1/BRCA2 Cancers

For patients with triple-negative breast cancer and BRCA1/BRCA2 mutations, current treatment options may at times be limited; currently, there are no specific treatments for BRCA1/BRCA2-mutated cancers that address the genetic defects seen in these cancers. However, there is growing interest in the use of Poly (ADP-ribose) polymerase (PARP) inhibitors in this setting.

Promise of PARP inhibition in BRCA-mutated disease

“In patients with BRCA1/BRCA2 mutations, PARP inhibitors are one of the most promising treatments to be tested recently in clinical trials,” says Jame Abraham, MD, Director of Cleveland Clinic Cancer Center’s Medical Breast Oncology Program and Co-Director of the Comprehensive Breast Cancer Program.

PARP inhibitors interfere with base excision repair and therefore DNA repair, to effect death of tumor cells. PARP inhibitors can be highly lethal to tumor cells in patients who already have impaired DNA repair from BRCA mutation, Dr. Abraham says.

Although triple-negative breast cancer can be sporadic, these cancers share traits that involve DNA repair defects with those occurring in BRCA-mutated carriers. Eighty percent of hereditary BRCA-mutated cancers share the triple-negative breast cancer phenotype. The prevalence of BRCA1 and BRCA2 mutations in triple-negative breast cancer ranges from 4 to 14.3 percent, and an additional 27 to 37 percent have somatic inactivation of BRCA1.

As a class, PARP inhibitors can cause profound damage to cancer cells in breast cancers that involve DNA repair pathway defects. A number of PARP inhibitors are undergoing clinical development, but none is yet FDA-approved for breast cancer.

OlympiAD and OlympiA: Clinical trial experience with olaparib

Cleveland Clinic is currently participating in two phase III clinical trials evaluating olaparib as a treatment for metastatic breast cancer as well as for stage II/III BRCA1/BRCA2, HER2-negative and triple-negative disease.

OlympiAD, the phase III trial on olaparib in metastatic breast cancer is ongoing but no longer recruiting participants and results are expected soon. In the meantime, Cleveland Clinic is enrolling patients in the OlympiA study, a phase III trial with olaparib as an adjuvant treatment for earlier-stage breast cancers with DNA repair defects — that is, in women with stage II and stage III breast cancer who have completed local treatment and neoadjuvant or adjuvant chemotherapy.

“We have enough evidence from metastatic breast cancer trials to know that olaparib is active in stage IV breast cancer. So now we want to see what kind of benefit stage II/III breast cancer patients will derive from use of olaparib,” Dr. Abraham says.

Olaparib was the first PARP inhibitor approved by both the FDA and the European Medicines Agency for patients with BRCA1/2 mutant ovarian cancer. In 2014, the FDA approved olaparib for patients with germline BRCA-mutated ovarian cancer who have undergone three or more lines of chemotherapy. The treatment was approved along with the BRACAnalysis CDx, a companion diagnostic test.

Read more at Cleveland Clinic

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