This is part of an ongoing series featuring interviews with physicians on topics related to hereditary cancer. This article was adapted from an interview with Kim Reiss Binder, MD. Dr. Reiss Binder is a medical oncologist and clinical researcher with the Basser Center for BRCA and the Abramson Cancer Center at the University of Pennsylvania. Dr. Reiss Binder’s area of expertise is BRCA-related pancreatic cancer. She leads several clinical trials that aim to improve the treatment options and outcomes for this group of patients.

Pancreatic Cancer Screening
Studies exploring the benefit of screening for pancreatic cancer in high-risk populations, such as in persons with inherited BRCA mutations, are ongoing. Obviously, this is an area of very high interest. For example, the CAPS5 study is following patients who undergo endoscopic ultrasound (EUS) every few months to try to identify lesions. They also aspirate fluid and look for early signs of mutations in the fluid of the pancreas. There are also trials at other institutions looking at magnetic resonance cholangiopancreatography (MRCP), MRI of the pancreas, at certain intervals to see if lesions can be found early.

If you know you’re high risk, such as if you have a mutation that predisposes you to pancreatic cancer and/or a family history of pancreatic cancer, it makes logical sense to want to begin early screening. At this moment in time, the data is not mature yet. In other words, the medical community cannot say with certainty that screening high-risk patients for pancreatic cancer every six months will lead to better survival for those who develop the disease. However, it you are interested in screening, we recommend you talk to your doctor about possibly enrolling in one of the ongoing clinical trials. If there is no clinical trial available to you, it still makes sense to discuss the consideration of screening tests with your physician.

Treatment Options: Platinum Chemotherapy
Treatments for pancreatic cancer are evolving. In the last eight years, various combinations of chemotherapy have been studied and are now used standardly to treat the disease. Some of the chemotherapy combinations contain platinum drugs like oxaliplatin and cisplatin. Several retrospective studies have shown that patients with BRCA or similar mutations have better clinical outcomes when they are treated with platinum-based chemotherapy. This is consistent with studies in other BRCA-related cancers. Therefore, we believe that if a patient with pancreatic cancer has a BRCA mutation, he should be treated with chemotherapy that contains platinum.

However, up until recently, our only option for patients with incurable pancreatic cancer was perpetual chemotherapy. Patients with BRCA related pancreatic cancer do exceptionally well, and can sometimes be on treatment for years. Therefore, there is a huge need to identify “maintenance” treatments that could maintain tumor control and be more tolerable for patients. 

PARP inhibitors are being actively explored as a possible maintenance treatment for patients.

Treatment Options: PARP Inhibitors
In BRCA-related breast, ovarian, and now prostate cancer, PARP inhibitors have been shown to be effective in multiple settings. Over the last few years, there were several small studies that evaluated possible activity of PARP inhibitors in BRCA-related pancreatic cancer. These studies suggested that PARP inhibitors might be effective for this group of patients, but there was, until very recently, no definitive data. In June of 2019, the POLO trial was released. This was a phase III trial that compared the PARP inhibitor olaparib (Lynparza) to a placebo in patients with germline BRCA mutations and incurable pancreatic cancer that was sensitive to platinum chemotherapy. Patients received four months of chemotherapy before being put on the study.  The trial showed that the patients who received olaparib had lack of tumor growth for twice as long as those who received the placebo, and about one in five patients had substantial shrinkage of their tumor during treatment with olaparib. Some patients stayed on the olaparib for years, showing that this treatment is extraordinarily effective for certain patients. However, when the two entire groups were compared, there was no difference in how long they lived. 

The takeaway from this study was that PARP inhibitors are certainly active against BRCA-related pancreatic cancer tumors, and that for some patients, these drugs are extraordinarily effective. However, many questions remain unanswered and should be part of the next generation of research studies. In particular: we need better methods, beyond just BRCA status, to identify the patients for whom PARP inhibitors are most effective. Second, we should explore combinations of PARP inhibitors with other therapies to test whether these might be more effective than a PARP inhibitor alone. Finally, we need to learn more about the evolving mechanisms within a tumor that might lead to resistance to PARP inhibitors – and we need to learn how to tackle them.

We are currently running two studies at the University of Pennsylvania that may help answer some of these questions. The first is the RUCAPANC2 trial, which is a study of the PARP inhibitor rucaparib in platinum-sensitive patients with either a BRCA or PALB2 mutation. This study also includes patients with “somatic” mutations, meaning not one that is inherited but rather occurs in the tumor alone. We hope that this study will help us identify more patients who might be eligible for PARP inhibitor therapy. The second trial is called the Parpvax trial, in which the PARP inhibitor niraparib is combined with either nivolumab or ipilimumab, two types of immunotherapy. This trial allows any patient whose cancer has become stable after treatment on platinum therapy – regardless of a BRCA mutation. We hope that for the patients with BRCA or PALB2 mutations that do enroll on the trial, this will help us address if this combination is better than a PARP inhibitor alone. And for patients without mutations, we hope it will identify additional persons who might benefit from this maintenance strategy.

Clinicians and scientists alike are very interested in what those maintenance drugs should be and how to find the appropriate patients. Now that people are living longer with metastatic disease, we’re compelled to do something better for them. That’s the next era of pancreatic cancer treatment.