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Professor of Oncology
University of Hamburg
Department of Oncology
Asklepios Tumorzentrum Hamburg
Dirk Arnold, MD, PhD, has disclosed that he has received consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, Pierre Fabre, and Roche; funds for research support from AstraZeneca, Bristol-Myers Squibb, and Pierre Fabre; fees for non-CME/CE services from Amgen, AstraZeneca, Bristol-Myers Squibb, MSD, Pierre Fabre, and Roche; and other financial or material support from AstraZeneca.
Inhibition of PARP, a key enzyme in the repair of single-stranded DNA breaks, is now an important treatment approach for select patients with pancreatic cancer. The PARP inhibitor olaparib is now approved by both the European Medicines Agency (EMA) and the FDA for the maintenance treatment of adult patients with metastatic pancreatic adenocarcinoma with germline BRCA mutations whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. In this commentary, I discuss my thoughts on the optimal use of PARP inhibition in the treatment of patients with pancreatic cancer.
Progress and Limitations With Chemotherapy
Progress in the treatment of metastatic pancreatic cancer has been slow. Over time, clinical research has extended OS in this patient population by intensifying chemotherapy with triplet regimens like FOLFIRINOX or the doublet regimen of nab‑paclitaxel and gemcitabine. However, the activity of these therapeutic regimens is somewhat limited, and patients usually become refractory within a year. Moreover, patients receiving these regimens can be heavily affected by associated adverse events, particularly if treatment is continued for an extended time, allowing the cumulative occurrence of toxicities like neuropathy. Given this clinical situation, the potential of using predictive markers to identify subsets of patients who may benefit from targeted therapies was a logical approach.
Targeting BRCA1/2 Mutations—POLO
Evaluation of thousands of patients with pancreatic cancer identified DNA damage response and repair pathway mutations as the most common genetic aberrations in this disease setting. In particular, overall approximately 5% to 7% of patients with pancreatic cancer have germline BRCA1 or BRCA2 mutations and consequently may benefit from treatment with PARP inhibitors, as seen in breast and ovarian cancers. Of note, the incidence of germline BRCA1 or BRCA2 mutations can be much higher in certain populations, including patients with Ashkenazi Jewish heritage and those with familial pancreatic, breast, or ovarian cancer syndromes. However, it is very important to realize that approximately 40% of patients with pancreatic cancer and a known germline BRCA1 or BRCA2 mutation do not have a discernible family history of cancer.
The international, randomized, double-blind phase III POLO trial compared the PARP inhibitor olaparib 300 mg BID vs placebo as maintenance therapy in patients with metastatic pancreatic cancer and known or suspected deleterious germline BRCA1/2 mutations who had received at least 16 weeks of first-line platinum therapy without evidence of disease progression. Overall, more than 3300 patients were screened for this trial, and only 7.5% had a germline BRCA1/2 mutation. This trial showed an approximate doubling of median PFS with olaparib maintenance therapy (7.4 vs 3.8 months with placebo; HR: 0.53), with a response rate of 23% and an impressive median duration of response of 24.9 months among the responding patients. A subgroup analysis showed similar PFS benefit regardless age, sex, BRCA1 or BRCA2 mutation, previous first-line chemotherapy, or response to first-line chemotherapy. Regarding adverse events, olaparib was generally well tolerated, with a moderately higher rate of overall toxicity, including predominantly fatigue/asthenia, gastrointestinal events, and anemia. Grade 3 or higher adverse events were uncommon, with anemia (11%) and fatigue/asthenia (5.5%) being the most frequent.
How do these findings and the recent approval of maintenance therapy with olaparib in both the United States and the European Union impact our clinical practice? I think that olaparib is now a standard of care for patients with metastatic pancreatic cancer and germline BRCA mutations with at least stable disease after 4 months of platinum-based chemotherapy. For this subgroup of patients, this approval leads to 2 key changes in our treatment algorithms.
First, and of importance, in patients who are responding to initial chemotherapy with symptom relief or who are not experiencing disease progression, the chemotherapy regimen, with its associated toxicities, can be discontinued, and the clinical benefit still maintained with the PARP inhibitor. This is very important for patients with metastatic pancreatic cancer, who often experience symptoms from the tumor, the chemotherapy treatment, or both. In contrast to our standard chemotherapy regimens, olaparib is very well tolerated, with few side effects, as noted above. Moreover, for those patients who do respond to olaparib therapy, the response is durable, as described above.
Second, the results from the POLO trial show that germline BRCA mutations are a strong predictor of clinical benefit for patients who received induction chemotherapy with an oxaliplatin‑based regimen followed by olaparib. Consequently, testing for germline BRCA1/2 mutations using a comprehensive gene panel is also now standard of care for patients with pancreatic cancer, especially those who are younger and able to tolerate intensive first-line platinum‑based combination chemotherapy. As mentioned above, germline BRCA mutations are not associated with any specific clinical characteristics, and can be present in many patients with no familial cancer syndromes, so all patients with metastatic pancreatic cancer should be tested. The primary question is, when should we request this testing for our patients? As our patients with metastatic pancreatic cancer generally present feeling sick, in pain, and having lost weight, waiting for a germline test result that may take approximately 1 month or longer is not going to be optimal. Thus, I do not hesitate to start these patients on an appropriate chemotherapy regimen that we know has been shown to improve survival and quality of life, sometimes fairly rapidly. But as I noted above, we also know that patients on first‑line chemotherapy have a median PFS of approximately 5-8 months, with some patients tolerating the chemotherapy for perhaps 3-4 months, so I use that window of time to initiate testing while they are on first-line chemotherapy.
Finally, although overall olaparib is well tolerated, as mentioned above, there are some side effects. In particular, olaparib is associated with fatigue and asthenia, which can also be related to both the previous treatment (ie, induction chemotherapy) and the disease itself. As a physician treating patients with metastatic pancreatic cancer, fatigue is the most difficult adverse event or symptom to manage. In our clinic, if patients do develop fatigue or asthenia on olaparib, I will pause their treatment for approximately 2 weeks; if they recover from the fatigue, I will restart treatment with a slightly lower dose, approximately 75% of the initial dose. So, for me, fatigue is really the key point, because it meaningfully affects patients’ quality of life, and I want to ensure I have not prescribed a drug that causes fatigue.
How has the availability of olaparib changed your clinical practice? Please answer the polling question and share your thoughts in the comment box below!