The prognosis of patients with metastatic pancreatic cancer (mPCA) remains poor, despite use of modern chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel/gemcitabine. After progression on frontline therapy, less than half of the patients are eligible for second-line treatment. There is a high, unmet need for targeted biomarker selected treatment approaches. In ovarian and breast cancer, presence of germline mutations in BRCA1 and BRCA2 genes are known to select for sensitivity to poly (ADP ribose) polymerase (PARP) inhibitors and maintenance treatment with olaparib is standard of care in these tumor types. Between 4% and 7% of patients with mPCA harbor germline BRCA mutations and may benefit from PARP inhibitor therapy.
During the plenary session at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Hedy Kindler, MD (University of Chicago, Chicago, Illinois, United States), presented results from the phase III POLO trial (Abstract LBA4), which compared olaparib to placebo as maintenance therapy following first-line platinum-based chemotherapy in 154 patients with mPCA with a germline BRCA mutation. These results were simultaneously published in The New England Journal of Medicine. Olaparib maintenance therapy (300 mg PO bid) resulted in a significant improvement in median progression-free survival (PFS) by blinded independent central review compared to placebo (7.4 months vs 3.8 months; HR 0.53, P = .0038). A greater proportion of patients receiving olaparib remained progression free at 6 months (53% vs 23%), 12 months (34% vs 15%), 18 months (28% vs 10%), and 24 months (22% vs 10%) postrandomization. In subgroup analyses, PFS favored olaparib maintenance in all patient subgroups with the exception of patients aged 65 years or older, and the benefit of olaparib was seen regardless of response achieved on first-line platinum chemotherapy (partial or complete response versus stable disease).
More patients responded to olaparib maintenance than to placebo (23.1% vs 11.5%), and the duration of response was longer among patients receiving olaparib (24.9 months vs 3.7 months). Overall survival (OS) data are not mature (46% maturity), but at interim analysis there was no benefit for olaparib over placebo (18.9 months vs 18.1 months; HR 0.91, P = .68). Time to second progression (PFS2) favored olaparib, but this was not statistically significant (13.2 months vs 9.2 months; HR 0.76, P = .26).
Grade 3 or higher adverse events (AEs) occurred more frequently in patients receiving olaparib (39.6% vs 23.3%). The most common all grade AEs in patients treated with olaparib include fatigue/asthenia (60.4% vs 35.0%), nausea (45.1% vs 23.3%), diarrhea (28.6% vs 15.0%), abdominal pain (28.6% vs 25.0%), and anemia (27.5% vs 16.7%). Anemia (11%) and fatigue (5.5%) were the most common grade 3 or higher AEs associated with olaparib maintenence. Importantly, there were no clinically meaningful changes in health-related quality of life in patients receiving olaparib maintenance compared to placebo (P = .31).
Dr Kindler concluded that olaparib maintenance following first-line platinum chemotherapy is well tolerated and associated with a statistically significant and clinically meaningful improvement in PFS in patients with BRCA-mutated metastatic pancreatic cancer and should become a new standard of care. The discussant for this abstract, Wells Messersmith, MD (University of Colorado Comprehensive Cancer Center, Denver, Colorado, United States), highlighted that this trial represents two major “firsts” in pancreatic cancer as the first successful biomarker-driven trial and the first successful trial of a maintenance therapy. He agreed that the 47% improvement in PFS with olaparib maintenance in BRCA-mutated mPCA is meaningful, despite the lack of survival benefit. He pointed out molecular tumor testing should be standard in mPCA and highlighted the need for future trials to examine the role of PARP inhibitors in mPCA with other DNA damage response and repair (DDR) alterations.