Johanna C. Bendell, MD
The incidence of pancreas cancer continues to rise in many countries.1
In 2017, an estimated 53,600 cases were diagnosed in the United States, representing an approximately 45% increase over the past decade.2,3
Pancreatic ductal adenocarcinoma (PDAC), which is considered incurable, accounts for more than 90% of pancreatic cancer cases.4
Amid this backdrop, a panel of experts from North America and Europe discussed emerging issues in the treatment of PDAC during an OncLive
program. Although the incidence of the disease has risen, “outcomes for patients with advanced PDAC have recently begun to improve, owing to refinement in the use of combination chemotherapy and new sequencing strategies for therapies,” said Johanna C. Bendell, MD, who moderated the session.
Despite the improvement, 5-year and 10-year survival rates for PDAC remain low,4 and new, more effective therapies are urgently needed. The panel members reviewed data from recent studies of novel therapies being evaluated in PDAC and shared their perspectives on the significance of the findings for clinicians and patients.
Evolving Approach to Drug Development
PDAC is a highly heterogeneous disease, according to Winson Y. Cheung, MD, MPH, who said the focus of drug development should be on “enriching the right patient subsets and targeting therapies to these individual groups” instead of treating everyone as though they had the same cancer. Tanios Bekaii-Saab, MD, FACP, predicted that patients with PDAC eventually will stratified into subgroups based on the degree of microsatellite instability (MSI) or presence of mutations that affect DNA damage response (DDR). Precision targeting has the potential to improve outcomes in PDAC.
Novel Targets Emerging
PARP and ATR Inhibitors
Manuel Hidalgo, MD, PhD, said that approximately 15% of patients with pancreas cancer harbor genetic mutations implicated in DDR dysfunction. Studies in patients with hereditary forms of pancreatic cancer have identified several defects in DDR, including mutations of BRCA1/2 genes; the ataxia telangiectasia mutated kinase (ATM) gene; and the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2. 5
However, Hidalgo said, “We’re learning more and more that even unselected cases have germline mutations in some of the genes that compose the [DDR] pathway.”
BRCA1/2 mutations appear to be the most prevalent genetic alterations in patients with PDAC, especially in those of Ashkenazi Jewish heritage.5
Although the exact prevalence varies between studies, 5% of unselected patients and 12% of Ashkenazi Jewish patients included in a recent single-center study harbored a BRCA1/2 mutation.5
Cells deficient in BRCA1 and BRCA2 proteins are sensitive to inhibitors of the poly (ADP-ribose) polymerase (PARP) enzyme, several of which have been approved by the FDA to treat patients with ovarian cancer. PARP inhibitors are now being studied for PDAC.6
Findings from an in vitro proof-of-concept study, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that a BRCA1-mutated, patient-derived xenograft model of pancreatic cancer responded strongly to monotherapy with the PARP inhibitor olaparib (Lynparza).7
In general, cell lines with DDR dysfunction were more sensitive to cisplatin, olaparib, and kinase inhibitors of ataxia telangiectasia and RAD3-related (ATR) gene activity.7
The in vitro study also showed that cell lines treated with the ATR inhibitor AZD6738 or the ATM inhibitor AZD0156, both of which are investigational, became sensitized to cisplatin.7 A phase II study of maintenance therapy with the PARP inhibitor rucaparib (Rubraca) in patients with advanced PDAC and a BRCA or PALB2 mutation began recruiting in June 2017.8STAT3 Inhibitors
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) upregulates antiapoptotic proteins, preventing apoptosis and contributing to the development and progression of pancreatic cancer.9
Thus, STAT3 is an emerging molecular target in PDAC. The novel agent napabucasin (BBI-608) is a STAT3 inhibitor that is also referred to as a stemness inhibitor. “[Stem cells] are supposed to be the hardiest, most stubborn cancer cells—they are essentially chemotherapy resistant and radiation resistant,” said BekaiiSaab.