Metastatic pancreatic cancer is a dismal disease. Even with modern chemotherapy regimens patients generally live less than a year. Historically, most do not receive second line treatment. There are no targeted therapies for this disease in a biomarker selected population validated by a phase III trial. 4-7% of pancreatic cancer patients harbour a germline BRCA1 or BRCA2 mutation. They obtain an increased benefit from platinum based chemotherapy. Maintenance treatments aim to delay disease progression following chemotherapy without compromising quality of life.
Olaparib is a PARP inhibitor that targets cancer cells that have a defect in DNA damage repair. The study design for POLO is shown here. Eligible patients had metastatic pancreatic cancer and a germline BRCA1 or 2 mutation. Patients had received at least 16 weeks of a first line platinum based chemotherapy without progression. There was no maximum limit to the duration of chemotherapy. 38% of the identified germline BRCA mutated patients had disease progression, were ineligible or declined randomisation, the remaining patients were randomised 3:2 to olaparib tablets 300mg orally twice daily or placebo and continued until investigator assessed disease progression or unacceptable toxicity.
The primary endpoint was progression free survival by blinded independent central review. Progression free survival was measured from time of randomisation which was after the completion of first line chemotherapy. Progression free survival was 7.4 months on the olaparib arm and 3.8 months on placebo with a hazard ratio of 0.53 and a p-value of 0.0038. This represents a 47% decrease in the risk of progression or death.
The objective response rate by blinded independent central review in patients with measurable disease was 11.5% for placebo and 23.1% for olaparib which included two complete responses. Time to onset of response was earlier in the placebo arm suggesting that these responses were a carry-over from first line platinum based chemotherapy. What is truly remarkable is that the median duration of response to olaparib in these patients who had metastatic pancreatic cancer was more than two years.
In conclusion, maintenance olaparib provided a statistically significant and clinically meaningful improvement in progression free survival to patients with a germline BRCA mutation and metastatic pancreatic cancer whose disease had not progressed during platinum based chemotherapy. Interim survival data showed no difference between arms. We are still awaiting final survival results which will be evaluated at 69% data maturity. Maintenance olaparib was well tolerated with an AE profile similar to that seen in other tumours. Health related quality of life was preserved with olaparib treatment and showed no difference between arms.
Our results are the first from a phase III trial to validate a targeted treatment in a biomarker selected population of pancreatic cancer patients, highlighting the importance of germline BRCA mutation testing in this setting. We conclude that a strategic approach of first line platinum based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation.
