The FDA has now approved olaparib (Lynparza®, AstraZeneca) for the maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma who have not experienced disease progression after at least 16 weeks of a first-line platinum-based chemotherapy regimen. In addition, the FDA approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) as a companion diagnostic for the selection of patients with deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations.
Deleterious mutations in the BRCA1 and BRCA2 genes are found in between 4% and 7% of patients with pancreatic cancer. Because they are deficient in homologous recombination repair, BRCA-mutated cells are susceptible to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors such as olaparib.
Approval was based on the phase 3 POLO trial (NCT02184195), in which 154 patients with metastatic pancreatic cancer and a germline BRCA1/2 mutation who had not experienced disease progression during first-line platinum-based chemotherapy were randomized in a 3:2 ratio to receive either maintenance olaparib tablets (300 mg twice daily) or placebo, for a primary end point of progression-free survival. Olaparib resulted in a median progression-free survival of 7.4 months, compared with 3.8 months for placebo. The overall response rate among patients with measurable disease at baseline was 23% for olaparib, compared with 12% for placebo. An interim analysis at a data maturity of 46% did not reveal a significant difference in median overall survival between the two trial arms (18.9 vs 18.1 months).
"Overall survival may be confounded by subsequent therapies, including that of the nine patients in the placebo group (15%) who went on to receive a PARP inhibitor after disease progression during the trial intervention," commented the study authors in their June publication in The New England Journal of Medicine, led by first author Talia Golan, MD, Head of the Sheba Pancreatic Cancer Center at the Oncology Institute of Tel Aviv University's Sheba Medical Center.
Eighty-nine of 92 patients in the olaparib arm and 58 of 62 patients in the placebo arm were included in analyses of health-related quality of life. There was no significant difference between groups in the adjusted mean change in Global Health Status score; in addition, there was no significant between-group difference in time to sustained clinically meaningful deterioration for either Global Health Status or physical functioning. Although there was a significant difference between groups in physical functioning, with higher physical functioning scores in the placebo arm, "this difference was not considered to be clinically meaningful based on the 10-point change threshold, and high baseline scores were preserved with olaparib treatment," stated the authors of the health-related quality of life analyses in their September publication in Annals of Oncology, led by first author Pascal Hammel, MD, Professor and Chief of Digestive Oncology at the Hôpital Beaujon, Paris.
Adverse reactions to olaparib occurring in at least 10% of patients in clinical trials include nausea, fatigue, vomiting, abdominal pain, anemia, diarrhea, dizziness, neutropenia, leukopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, stomatitis, dyspnea, and thrombocytopenia.
The recommended dose of olaparib is 300 mg, taken orally twice a day with or without food.
For More Information
Hammel P, Kindler HL, Reni M, et al (2019). Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Ann Oncol, 30(12):1959-1968. DOI:10.1093/annonc/mdz406Image credit: Min Yu, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. Courtesy of the National Cancer Institute / USC Norris Comprehensive Cancer Center