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Assistant Professor of Medicine
Chief, Section of GI Medical Oncology
Director, UACC Clinical Trials Office
The University of Arizona Cancer Center
Rachna Shroff, MD, has disclosed that she has received consulting fees from Agios/Clovis, Debiopharm, Exelixis, Incyte, Merck, QED Therapeutics, and Seattle Genetics and funds for research support from Exelixis, Merck, and Pieris/Taiho/Rafael.
The management of patients with advanced pancreatic cancer has—both in the locally advanced and unresectable/metastatic spaces—predominantly been defined by the use of chemotherapy. However, actionable molecular alterations and associated targeted therapeutics are beginning to emerge, offering new treatment options for some patients. In this commentary, I review the current state of targeted therapy for advanced pancreatic cancer and discuss how I employ molecular testing and targeted treatments in my practice.
Current Treatment Paradigms and Emerging Targeted Therapies
At present, FOLFIRINOX and gemcitabine plus nab-paclitaxel should be considered as first-line chemotherapy options for patients with advanced, unresectable disease without actionable mutations, with nanoliposomal irinotecan plus 5-FU/LV recommended for patients who require second-line therapy after gemcitabine plus nab-paclitaxel. Note that gemcitabine plus nab-paclitaxel can be considered for patients who have previously received FOLFIRINOX. I think it’s safe to say that these regimens will remain an important backbone of treatment for a very long time.
However, research is beginning to define the role of targeted therapy and immunotherapy for advanced pancreatic cancer. The molecular landscape that drives the development of pancreatic cancer is incredibly complicated, but with advances in our understanding, we have gained a better understanding of how we can leverage specific molecular alterations in drug development. Through efforts like the Know Your Tumor program and other large‑scale molecular profiling studies, we have learned that 15% to 25% of pancreatic cancers have alterations in DNA damage repair pathways. These alterations include BRCA mutations, which are typically associated with breast and ovarian cancer syndromes but found not infrequently in pancreatic cancer. The finding that BRCA mutations occur in pancreatic cancer led to testing of PARP inhibitors as therapeutics for patients with BRCA mutations and, recently, the FDA approval of maintenance therapy with the PARP inhibitor olaparib. This represented the first specific targeted therapy indicated for patients with pancreatic cancer. The approval of olaparib was based on the phase III POLO study, which randomized patients with metastatic pancreatic cancer with a deleterious/suspected deleterious germline BRCA1/2 mutation who had received ≥4 months of first-line platinum-based therapy without progression to maintenance therapy with olaparib or placebo. This study demonstrated that progression-free survival (primary endpoint) was significantly improved with olaparib maintenance therapy, but median overall survival was similar between arms. It is now part of our treatment algorithm to have all patients diagnosed with pancreatic cancer undergo genetic counseling and germline testing to look for the presence of BRCA mutations.
Using PARP Inhibitors
The FDA approval of olaparib was a huge step forward in pancreatic cancer, representing the first targeted therapy available to our patients. The POLO study was deemed positive because the primary endpoint of improved progression‑free survival with olaparib was met. Overall survival, however, was not improved with the targeted agent. As such, the POLO study has been met with several criticisms, including those regarding the use of placebo as a control arm vs continued maintenance chemotherapy and final overall survival data not showing a statistically significant improvement with olaparib. Regarding the latter criticism, many patients in the placebo group went on to receive PARP inhibitors outside of the study, which may have caused some noise in terms of understanding the overall survival data.
Despite these criticisms, when I am considering treatment for a patient with a BRCA‑mutated tumor and platinum‑sensitive advanced disease, the concept of switching from an every-2‑week chemotherapy such as FOLFIRINOX—which is administered via IV infusion and includes 2 days of carrying around a pump at home—to oral olaparib is appealing. This is borne out in the quality-of-life data from POLO, which support the concept of switching from IV chemotherapy to oral therapy for convenience. I absolutely consider maintenance olaparib in the clinic for platinum‑sensitive patients. More than anything, the approval of maintenance olaparib gives us another tool in our treatment toolbox. At the end of the day, we have limited therapeutic options for patients with advanced pancreatic cancer. Anything we can do to “save” treatments can help prolong survival in these patients, allowing them to remain platinum sensitive with the option to return to a platinum-based regimen should this be necessary due to disease progression or other issues. For me, the use of olaparib is not just about hard-and-fast clinical endpoints such as overall survival and progression‑free survival, but also about quality-of-life considerations.
Testing for Molecular Alterations
Beyond BRCA mutations, other defects in DNA damage repair pathways—including PALB2 mutations—appear to be potentially actionable. In addition, the PD-1 inhibitor pembrolizumab has a tumor-agnostic indication for patients with microsatellite instability–high/mismatch repair deficient or tumor mutational burden–high advanced solid cancers for which previous treatments have failed. Similarly, the TRK inhibitors larotrectinib and entrectinib have tumor-agnostic indications for patients with advanced solid cancers with NTRK fusions for which previous treatments have failed. These molecular alterations rarely occur in pancreatic cancers, but when they do, these agents have the potential to offer benefit for patients. Clinical trials assessing numerous other targeted therapies are also ongoing.
Major treatment guidelines now recommend germline and somatic testing for potential actionable mutations in all patients with advanced pancreatic cancer. I absolutely refer every single one of my patients to our genetics counselors at the time of diagnosis, and I try to use next-generation sequencing platforms (both liquid biopsy–based and tissue based) to assess potentially actionable targets for which we have either FDA-approved treatments or therapies being assessed in ongoing clinical trials.
As our understanding of actionable mutations in pancreatic cancer continues to grow, making sure that our patients with advanced pancreatic cancer receive molecular testing to fully understand potential targets and available therapies is going to be an important part of an overall treatment strategy. Targeted therapy should not replace chemotherapy at this time, so FOLFIRINOX, gemcitabine plus nab‑paclitaxel, and nanoliposomal irinotecan plus 5-FU/LV should all be considered standard options for our patients with advanced pancreatic cancer. At present, olaparib should be considered in the maintenance setting after upfront platinum-based chemotherapy for patients with germline BRCA mutations, and other approved options, including immune checkpoint and TRK inhibitors, should be considered following chemotherapy for patients with specific molecular alterations. That said, ordering molecular testing at the time of diagnosis should be a standard approach as we continue to see evolution in our understanding of biomarker testing and targeted therapies.