2021 TDDW
Special Lecture (VIII) THE ROLE OF OLAPARIB IN MANAGEMENT OF PATIENTS WITH GERMLINE BRCA-MUTATED METASTATIC PANCREATIC CANCER Talia Golan Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. The median overall survival (OS) in patients with stage IV disease is limited. This disease is a challenge, with patients presenting with severe debilitating symptoms at diagnosis, including weight loss, radiating abdominal pain, loss of appetite, depression and deteriorated physical activity and well-being. Furthermore, PDAC is resistant to chemotherapy, with 4-6 months of progression free survival or less with first-line combination chemotherapy therapy. To improve the management of PDAC in an era of precision medicine, it is highly important to identify subsets of patients who can benefit from targeted treatments. In particular, BRCA 1/2 germline mutations (gBRCAm) affect up to 7% of patients with PDAC. The BRCA 1/2 proteins play a significant role in the repair of DNA double strand breaks (DSB). Tumors with homologous recombination repair (HRR) gene abnormalities such BRCA1/2 are sensitive to both platinum and poly (ADP-ribose) polymerase inhibitors (PARPi). In the phase III POLO study (Pancreas Cancer Olaparib Ongoing), the PARPi olaparib was given as maintenance treatment following firstline platinum-based chemotherapy in gBRCAm patients with metastatic PDAC versus placebo. Patients had to receive at least 16 weeks of firstline, platinum-based chemotherapy, without tumor progression. 154 eligible patients for the POLO trial were randomized at a 3:2 ratio to olaparib tablets, 300 mg po bid, or placebo, and continued treatment until disease progression or unacceptable toxicity. The primary endpoint was PFS and was measured from the time of randomization, which
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was after first-line chemotherapy had been completed. Key secondary endpoints included time to second progression, objective response rate, health-related quality of life, safety and tolerability, and overall survival. The primary endpoint (PFS) was 7.4 months in the olaparib arm, and 3.8 months in the placebo arm, with a hazard ratio of 0.53, and a p value of 0.0038. Pre-specified analyses were performed of the proportion of patients who were progressionfree at 6, 12, 18 and 24 months. From 6 months onwards, more than twice the proportion of olaparib arm patients were progression-free compared to the placebo arm, which is consistent with the hazard ratio of 0.53. Although the secondary endpoint, OS did not demonstrate a statistically significant difference between olaparib and placebo (HR 0.83; p = 0.3487), the totality of the evidence (primary PFS and multiple key secondary endpoints) supports a clinically meaningful benefit of maintenance olaparib in patients with metastatic pancreatic cancer and a gBRCAm. At 3 years: 17.2% of patients remained on olaparib treatment vs 3.3% on placebo. 21.5% of patients in the olaparib arm remained free of subsequent cancer therapy vs 3.6% in the placebo arm (TFST: HR 0.44, nominal p < 0.0001) and 33.9% of patients receiving olaparib were alive compared with 17.8% on placebo. These results confirm the importance of testing for BRCA and other germline mutations in all PDAC patients, which is now recommended by both ASCO and NCCN guidelines. A strategic approach with first-line platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic PDAC patients who have a gBRCAm.
