Abstract IA10: Targeting the DNA damage response in cancer: Progress in the clinic
Authors: Yap Timothy A. 
Published: May 2017

Genomic instability is a recognized hallmark of cancer and is associated with a predilection for cumulative DNA damage. In contrast to cytotoxic chemotherapy and radiotherapy, targeting critical aberrations involved in the DNA damage response (DDR) of cancer cells permits greater tumor selectivity against tumors with deficient DDR function, while sparing normal tissue. Poly(ADP-ribose) polymerase (PARP) inhibitors are the first class of antitumor agents to exploit cellular weaknesses in DNA repair through the concept of synthetic lethality.

Since the pivotal studies in 2005 that demonstrated the exquisite sensitivity of BRCA1 and BRCA2 (BRCA1/2) mutant cell lines and xenografts to PARP inhibition, great progress has been made in developing single agent PARP inhibitors for use in the Clinic. Early phase clinical trials demonstrated that olaparib was well tolerated, with single agent activity in patients with BRCA1/2 mutation ovarian, breast, pancreatic and castration-resistant prostate cancers. In 2014, olaparib (Lynparza; AstraZeneca) was the first PARP inhibitor to be approved by the European Medicines Agency (EMA) as maintenance therapy for responding patients with BRCA1/2 mutant ovarian cancer following platinum-based chemotherapy, and the first to obtain accelerated approval by the US Food and Drug Administration (FDA) for advanced BRCA1/2 mutant ovarian cancer. There are also multiple other potent and bona fide PARP inhibitors, including rucaparib (AGO14699; Clovis), talazoparib (BMN673; Medivation), niraparib (MK4827; Tesaro) and veliparib (ABT-888; Abbvie), which are all currently in late phase clinical trial development.

A number of critical questions remain in terms of optimizing and widening the clinical efficacy and utility of PARP inhibitors, respectively. While benefits are observed following PARP inhibitor treatment in patients with a range of tumor types with germline BRCA1/2 mutations, it is now clear that clinical efficacy is not restricted to this niche population of patients. Potential antitumor strategies may include successfully characterizing other predictive biomarkers of response or defining unique PARP inhibitor combination regimens. Such novel combinations include those with molecularly targeted agents against the PI3K-AKT and angiogenic pathways, as well as immune checkpoint inhibitors.

Apart from PARP inhibitors, other novel antitumor agents against key DDR targets such as ATR and Wee1 kinase are showing promise in early phase clinical trials. The first-in-class ATR inhibitor VX-970 (Vertex Pharmaceuticals) was well tolerated as monotherapy and in combination with carboplatin chemotherapy, with preliminary evidence of target modulation and early signals of antitumor activity in DDR aberrant cancers. VX-970 is currently being explored in early phase I/II studies involving multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations. AZD1775 (AstraZeneca) is a first-in-class Wee1 inhibitor, which was well tolerated with preliminary single-agent activity in patients harboring BRCA1/2 mutations. AZD1775 was also well tolerated in combination with carboplatin chemotherapy, with promising antitumor activity in p53 mutated ovarian cancer refractory or resistant to standard first line therapy.

Citation Format: Timothy A. Yap. Targeting the DNA damage response in cancer: Progress in the clinic. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA10.