POLO Will Change Practice in Pancreatic Cancer

CHICAGO — PARP inhibitor maintenance is set to become the new standard of care in metastatic pancreatic cancer patients with platinum-sensitive disease and germline BRCA mutations, researchers and experts said here.

For such patients in the phase III POLO trial, those randomized to olaparib (Lynparza) had a median progression-free survival of 7.4 months compared with 3.8 months with placebo (HR 0.53, 95% CI 0.35-0.82, P=0.004), reported Hedy Kindler, MD, of the University of Chicago Medicine.

At 2 years, 22.1% in the olaparib arm had no disease progression compared with 9.6% in the placebo arm.

“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 mutation,” Kindler said during a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

The objective response rate was 23.1% in the treatment arm and 11.5% in the placebo arm, and median durations of response were 24.9 and 3.7 months, respectively.

The findings were published simultaneously in the New England Journal of Medicine.

“This is really a huge step forward,” ASCO-designated expert Suzanne Cole, MD, of UT Southwestern Medical Center in Dallas, said during the briefing. “This is the first time that a targeted medication has been successful in stopping the growth from metastatic pancreatic cancer in people who carry the BRCA mutation.”

More olaparib-treated patients saw their disease go “dormant,” she said, with 20% still alive and achieving excellent disease control at 2 years.

“It is out duty to search for this genetic mutation in all patients with metastatic pancreatic cancer,” said Cole. “This is practice-changing for people who have the BRCA mutation.”

With this approach becoming standard in BRCA-positive breast and ovarian cancers, Charles Fuchs, MD, MPH, director of the Yale Cancer Center, told MedPage Today that he too anticipates it will “emerge as a standard of care” in pancreatic cancer. He said the importance of this study is it shows that if the biology of this difficult-to-treat disease is better understood, therapeutic strategies can be found that “move the needle.”

“You can only stay on platinum-based therapies for a limited amount of time because of various side effects,” said Fuchs. “I think if you look at the approach in total — namely the approach of giving a platinum-based chemotherapy followed by maintenance PARP inhibitor — what the study shows is those patients had a progression-free survival to what appears in excess of 1 year, which is pretty impressive.”

Overall survival data, immature at the time of the presentation, showed no significant difference between the two groups, at 18.9 months with olaparib versus 18.1 months with placebo (HR 0.91, 95% CI 0.56-1.46, P=0.68). But Fuchs pointed that while the trial didn’t allow for crossover, 15% of patients in the placebo arm went on to receive a PARP inhibitor following disease progression anyhow, which could confound the data.

National Comprehensive Cancer Network (NCCN) guidelines now recommend pancreatic cancer patients receive genetic testing, and according to previous research, roughly 5% to 8% of patients with pancreatic cancer have genes that cause homologous recombination deficiency — germline or somatic mutations in BRCA1/2, PALB2, and others. These mutations confer heightened sensitivity to platinum-based chemotherapies and PARP inhibition.

A small study of 19 patients was presented at the 2019 American Association for Cancer Research in Atlanta, and also showed benefit with the PARP inhibitor rucaparib (Rubraca) in metastatic pancreatic cancer patients, but differed in that patients with PALB2 mutations were also enrolled, as were those with somatic BRCA mutations.

Kindler said the goal for the future will be to identify additional patients that could benefit from this strategy.

The POLO trial initially screened 3,315 metastatic pancreatic cancer patients. Of these, 247 had a germline BRCA mutation, but 80 were excluded due to either progression, death, trial eligibility criteria, or physician or patient choice. After at least 16 weeks of platinum-based chemotherapy, 154 patients were randomized 3:2 to either 300 mg olaparib twice daily or placebo and treated until disease progression or unacceptable toxicity.

Median patient age in the study was 57. BRCA1 mutations were present in 32% of patients in investigational arm and 26% of patients in the control arm, with the rest having BRCA2 mutations. More than 80% of patients in each group had received FOLFIRINOX chemotherapy in first-line, or a variant of the standard treatment. Median duration of first-line treatment was about 5 months in each arm, with about one-third in each arm receiving at least 6 months of treatment.