Olaparib, the First PARP Inhibitor to Gain FDA Approval to Treat BRCA-mutant Breast Cancer

On January 12, 2018, the FDA granted regular approval to LYNPARZA® (olaparib) for the treatment of patients with a deleterious, or suspected deleterious, germline BRCA 1 or BRCA 2 mutation (gBRCAm), who have human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) and have received prior chemotherapy in the neoadjuvant, adjuvant or metastatic setting [1]. Wild type BRCA1 and BRCA 2 proteins function as tumor suppressors by supporting DNA repair pathways in cells, thus preventing an accumulation of mutations that may lead to cancer [2]. gBRCAms can result in dysfunctional BRCA1 or BRCA2 proteins and have been implicated in several cancer types including ovarian, breast, prostate, and pancreatic [3]. Tumor cells that lack functional BRCA1 or BRCA2 protein are acutely dependent on other DNA repair molecules such as poly ADP-ribose polymerase (PARP) for proliferation and survival, and are therefore uniquely sensitive to PARP inhibition, a phenomenon known as synthetic lethality [4].

Olaparib (marketed by AstraZeneca), as well as other PARP-specific small molecule inhibitors, have already been approved for the treatment of various types of ovarian cancer, but this approval marks the first of its kind for breast cancer patients. The approval was based on results from a randomized, open-label phase 3 trial, OlympiAD, that compared olaparib monotherapy to standard chemotherapy for patients with gBRCAm-positive, HER2-negative, relapsed or refractory breast cancer (NCT02000622O) [5]. Those who received olaparib demonstrated a progression free survival (7 months vs. 4.2 months, respectively) and response rate (59.9% vs. 28.8%) benefit over patients who received standard single agent chemotherapy [6]. Additionally, the safety profile of olaparib was found to be superior to standard chemotherapy in this study with 36.6% and 50.5% of patients experiencing grade 3 or higher adverse events, respectively. This approval provides hope for patients who typically have few therapeutic options available to them and paves the way for similar agents in this space.

–Zachary Moore, on behalf of the Medical Content Team

1. LYNPARZA (olaparib) tablets. Drugs@FDA: FDA Approved Drug Products 01/12/2018 [cited 2018 April 6]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf.
2. Chen, J., et al., Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell, 1998. 2(3): p. 317-28.
3. Paul, A. and S. Paul, The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci (Landmark Ed), 2014. 19: p. 605-18.
4. Ceccaldi, R., et al., Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature, 2015. 518(7538): p. 258-62.
5. Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations. (OlympiAD). ClinicalTrials.gov February 26, 2018 [cited 2018 April 9]; Available from: https://clinicaltrials.gov/ct2/show/NCT02000622.
6. Robson, M., et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med, 2017. 377(6): p. 523-533.