Significant progress has been made in treating one of the most aggressive and difficult-to-cure cancers: the treatment is indicated for patients with a BRCA mutation (who represent 7% of cases).
There’s a notable advancement in the treatment of one of the most aggressive cancers, metastatic pancreatic adenocarcinoma, even though it applies to a subset of patients. The Italian Medicines Agency (AIFA) has approved reimbursement for olaparib, a targeted therapy and the first in a class of PARP inhibitors, for maintenance treatment of patients with metastatic pancreatic adenocarcinoma who have BRCA1/2 mutations and have not experienced disease progression after at least 16 weeks of first-line platinum-based chemotherapy. In 2024, an estimated 13,585 new cases of pancreatic cancer were reported in Italy, with approximately 7% presenting with BRCA1/2 gene mutations. In this patient population, olaparib demonstrated a 47% reduction in the risk of disease progression in the POLO study.
The POLO Study
“Metastatic pancreatic adenocarcinoma is one of the cancers with the most unfavorable prognosis, characterized by late diagnosis, an extremely rapid clinical course, and a significant impact on patients’ quality of life,” explains Michele Reni, director of Medical Oncology at the IRCCS San Raffaele Hospital in Milan and associate professor of Oncology at the Vita-Salute San Raffaele University. “The international phase III POLO study, published in the New England Journal of Medicine, involved 154 patients with pancreatic adenocarcinoma with germline mutations in the BRCA1/2 genes, who had received at least 16 weeks of first-line chemotherapy with platinum-based drugs without disease progression. Progression-free survival nearly doubled with olaparib, reaching 7.4 months compared to 3.8 months with placebo. This is a statistically significant result: to date, no maintenance treatment for pancreatic cancer has improved progression-free survival. Three-year survival was 33.9% for olaparib compared to 17.8% with placebo.” This finding offers new hope for a patient population with limited treatment options.
BRCA Mutation Testing
POLO is the first study to establish a benefit with a molecularly targeted drug based on a genetic mutation in pancreatic carcinoma. “This opens up a path already taken successfully in other cancers, where patients receive therapies based on mutations in the genetic and molecular profile,” continues Reni, who is one of the study’s authors. “it is essential that testing for BRCA mutations is guaranteed for all patients at the time of diagnosis of pancreatic cancer.” This isn’t always the case in Italy, where access to BRCA testing can vary. The BRCA genes (which became “famous” for prompting actress Angelina Jolie to undergo a mastectomy and removal of her fallopian tubes and ovaries to avoid cancer) are not just a “women’s issue” since they have been linked to an increased risk of developing cancer of the breast, ovary, prostate, and pancreas. And it doesn’t just affect patients, but also their healthy family members: “A positive BRCA test in a newly diagnosed patient with pancreatic adenocarcinoma not only influences the choice of therapy, i.e., platinum-based chemotherapy followed by olaparib, but also allows for the timely identification of family members carrying the same mutation, allowing them to be included (if necessary) in prevention and surveillance programs for the various cancers that can develop as a result of a mutation in the BRCA genes.”
Reduced Risk of Death
Pancreatic cancer is one of the most difficult to treat and complex to diagnose. There are no screening tests available, and the disease usually manifests with late symptoms, when it is already widespread. Only 20% of cases are diagnosed at an early stage, when surgery can still lead to a cure. Despite improvements in chemotherapy and supportive therapies, the prognosis for pancreatic adenocarcinoma remains among the worst of solid tumors. “The management of advanced pancreatic adenocarcinoma has been based for decades on chemotherapy, with a significant toxicity burden for prolonged treatments and relatively few options for patients who no longer respond to first-line treatment,” adds Michele Milella, director of Oncology at the Integrated University Hospital of Verona. “scientific research has focused on identifying the molecular targets underlying the disease, such as the BRCA genes, which increase the risk of developing not only breast, ovarian, and prostate cancers, but also pancreatic cancer.” Data from an independent Italian real-world study, published in Cancer Medicine, led to the long-awaited approval of reimbursement for olaparib. “The investigation involved 23 oncology departments distributed throughout the country and included 114 patients. The objective was to collect real-world data to assess whether the use of olaparib, both as maintenance in the first line as indicated and in more advanced lines of therapy, was associated with a significant and clinically relevant prolongation of overall survival in patients with metastatic pancreatic adenocarcinoma carrying BRCA1/2 mutations. In patients who received olaparib in any line of treatment, including maintenance therapy in the absence of progression after chemotherapy, as in the POLO study, the greatest survival benefit was demonstrated, with a 43% reduction in the risk of death. These data confirm, in daily clinical practice, the value of the drug already emerged in the registration study.”
