Highlights from

ASCO 2019

American Society of Clinical Oncology annual meeting

Chicago, USA 31 May - 4 June 2019

Maintenance olaparib improved PFS in patients with BRCA+ pancreatic cancer

Medical writer: Tim Donald, ELS

Maintenance therapy with olaparib prolonged progression-free survival (PFS) of metastatic pancreatic cancer (MPC) with a germline BRCA mutation in the randomized, phase III POLO trial. Olaparib, which was administered following first-line treatment with platinum-based chemotherapy, was well tolerated, and health-related quality of life (HRQOL) was preserved compared with placebo. Hedy L. Kindler, MD, FASCO, of The University of Chicago, presented these results (Abstract LBA4) during the June 2 Plenary Session.

“Our results are the first from a phase III trial to validate a targeted treatment in a biomarker-selected population of patients with pancreatic cancer, highlighting the importance of germline BRCA mutation testing in this setting,” Dr. Kindler said. “We conclude that a strategic approach of first-line platinum-based chemotherapy followed by olaparib treatment should become a new standard of care for patients with MPC who have a germline BRCA mutation.”

No targeted treatment for MPC in a biomarker-selected population has been validated in a phase III trial, Dr. Kindler noted. Approximately 4% to 7% of patients with MPC have a BRCA1 and/or BRCA2 mutation.

“This is a huge step forward for patients with MPC,” ASCO Expert Suzanne Cole, MD, of The University of Texas Southwestern Medical Centre, said during a press briefing earlier in the day. “This is the first time that a targeted medication has been successful at stopping the growth of MPC in people who carry the BRCA mutation. More patients with MPC who also have a BRCA mutation saw their disease go dormant when they received olaparib.” Dr. Cole further noted that “at 2 years, 20% of patients were still alive, with excellent disease control, because they were taking olaparib.”

Dr. Cole said “it is now our duty” to search for this mutation in all patients with MPC, in order to identify those who can benefit from treatment with this oral agent.

The international, double-blind POLO trial enrolled patients with a germline BRCAmutation and metastatic pancreatic adenocarcinoma who had received 16 weeks or more of first-line platinum-based chemotherapy without progression. Of 3,315 patients screened for the study, 247 (7.5%) were identified to have a germline BRCAmutation. Of those, 154 patients were randomly assigned 3:2 to receive maintenance oral olaparib (300 mg twice daily; 92 patients assigned, 90 treated) or placebo (62 patients assigned, 61 treated). Maintenance was continued until disease progression or unacceptable toxicity. Patient characteristics were well balanced between arms.

The primary endpoint was PFS by blinded independent central review using modified RECIST version 1.1 criteria. Secondary endpoints included time to second progression, objective response rate, HRQOL, safety and tolerability, and overall survival (OS).

With 104 events recorded, PFS was significantly improved with olaparib compared with placebo (HR 0.53, 95% CI [0.35, 0.82]; P = 0.0038) with a median of 7.4 months in the olaparib arm and 3.8 months in the placebo arm.

“This represents a 47% decrease in the risk of progression or death,” Dr. Kindler said.

At the data cut off of January 15, 2019, 30 patients receiving olaparib (32.6%) and 12 patients receiving placebo (19.4%) were progression-free. From 6 months onward, more than twice as many patients in the olaparib arm progression-free, compared with the placebo arm, Dr. Kindler said.

At the interim OS analysis, the median OS was 18.9 months in the olaparib arm and 18.1 months in the placebo arm (HR 0.91, 95% CI [0.56, 1.46]; P = 0.68). The OS data were at 46% maturity, with the final OS analysis planned at 106 events.

Objective response was seen in 23.1% of patients in the olaparib arm and 11.5% in the placebo arm. Two patients in the olaparib arm had a complete response, both of which were ongoing at data cut off, Dr. Kindler said.

“What is truly remarkable is that the median duration of response to olaparib in these patients who had MPC was more than 2 years,” she said. Specifically, median duration of response was 24.9 months in the olaparib arm and 3.7 months in the placebo arm.

The effect size for the primary endpoint of PFS in the trial was “impressive,” Dr. Messersmith said, especially in the setting of pancreatic cancer. Side effects in the study were manageable, especially compared to those with cytotoxic agents, and adverse events were similar to those seen in other trials of PARP inhibitors.

The POLO trial accomplishes several “firsts” in pancreatic cancer, he said. POLO is the first successful biomarker-driven trial with a germline mutation, and the first successful maintenance trial design—an approach that is rare with MPC.

One important implication of the study, Dr. Messersmith said, is that molecular testing should be standard for patients with advanced pancreatic cancer.

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.