ABSTRACT
Lynparza™ (olaparib) is a potent poly ADP-ribose polymerase (PARP) inhibitor. PARP enzymes are essential for the repair of DNA single-strand breaks (SSBs), and when PARP is inhibited, these SSBs become DNA double-strand breaks (DSBs). If these DSBs are not repaired by an appropriate mechanism, such as homologous recombination repair (HRR), they result in genomic instability and cell death. Tumors with a defect in HRR, such as those harboring mutations in BRCA1 or BRCA2 (BRCA1/2), are thus sensitive to the effects of PARP inhibition.
This section discusses the early development of olaparib in the BRCA1/2-mutated ovarian cancer population based on understanding this biological rationale. In particular, we focus on the challenges of delivering the regulatory approval of a BRCA1/2 mutation test as a companion diagnostic (CDx) in the United States through the premarket approval (PMA) process. Despite the challenges, Myriad’s BRACAnalysis CDx was contemporaneously approved with AstraZeneca’s olaparib in 2014. This marked the first regulatory approval of a laboratory developed test (LDT) and the first approval of a mutation test for complex tumor suppressor genes as CDx under a PMA paving the way for the delivery of further complex biomarkers and LDTs as regulatory-approved CDxs.
