PFS Increased With Olaparib as Maintenance Therapy for BRCA+ Metastatic Pancreatic Cancer

Jose Baselga, MD, PhD

The PARP inhibitor olaparib (Lynparza) significantly improved progression-free survival (PFS) in patients with germlineBRCA-mutated metastatic pancreatic cancer compared to placebo when used as maintenance therapy in the phase III POLO trial, presented at the 2019 ASCO Annual Meeting.^1,2

Overall, the median PFS was 7.4 months with olaparib versus 3.8 months with placebo (hazard ratio [HR], 0.53; 95% CI, 0.35-0.82;P= .004).

“This is the first positive phase III trial of any PARP inhibitor in germlineBRCA-mutated metastatic pancreatic cancer, a devastating disease with critical unmet need. Most patients are diagnosed late, leaving them with a poor prognosis and very limited treatment options. Based on POLO, Lynparza becomes the first PARP inhibitor to demonstrate positive phase III results beyond ovarian cancer and breast cancer,” José Baselga, MD, PhD, executive vice president, Research and Development, Oncology, AstraZeneca, said in a press release announcing the positive data in February.³

In the randomized, double-blind, placebo-controlled, phase III trial, researchers evaluated the efficacy of olaparib as maintenance therapy in 154 patients who had a germlineBRCA1orBRCA2mutation and metastatic pancreatic cancer, which had not progressed during first-line platinum-based chemotherapy.

Patients were randomized 3:2 to receive oral olaparib tablets at 300 mg twice daily as maintenance therapy (n = 92) versus placebo, also twice daily (n = 62). Randomization occurred within 6 weeks following last chemotherapy dose and olaparib/placebo treatment began within 4 to 8 weeks of the last chemotherapy dose. Following randomization, patients had weekly clinical visits for the first 4 weeks of treatment, then every 4 weeks while on study treatment.

The median duration of treatment was 6 months for those taking olaparib and 3.7 months for people who received a placebo. Treatment continued until objective radiological disease progression. Following progression, patients were followed for second progression every 8 weeks, and then for survival until final analysis.

Eligible patients were previously treated for metastatic disease and had not progressed following completion of at least 16 weeks of frontline platinum-based chemotherapy. Additionally, patients had to have a known deleterious or suspected deleterious germlineBRCAmutation. Those who were previously treated with a PARP inhibitor were excluded.

The primary endpoint was PFS by blinded independent central review. Secondary endpoints were overall survival (OS), time from randomization to second progression or death, objective response rate (ORR), disease control rate (DCR), safety, and tolerability.

Patients in the treatment arm were a median age of 57 years, 58% were male, and 71% had an ECOG performance status of 0. Two-thirds of patients hadBRCA2mutations, and the remainder hadBRCA1mutations.

Median PFS was consistent irrespective of response to prior platinum-based chemotherapy (complete/partial HR, 0.62; stable disease HR, 0.50). At 6, 12, 18, and 24 months, the percentage of patients who were progression-free in the olaparib arm was more than twice that in the placebo arm (6-month PFS, 53% vs 23%).

The ORR was 23.1% with olaparib compared with 11.5% in the placebo arm. Two patients treated with olaparib had a complete response, both of which were ongoing at data cutoff. The median duration of response was 24.9 months in the olaparib arm versus 3.7 months with placebo.

After 1 year, 33.7% of patients receiving olaparib showed no signs of disease progression compared with 14.5% of those who received a placebo.

An interim analysis of OS at data maturity of 46% demonstrated no difference between arms (median OS, 18.9 vs 18.1 months; HR, 0.91; 95% CI, 0.56-1.46;P= .68).

In addition, the researchers saw no significant difference in health-related quality of life.

There were no new safety signals with olaparib. Grade 3 or higher adverse events (AEs) occurred in 40% of patients in the olaparib arm compared with 23% of those in the placebo arm (95% CI, −0.02% to 31%). In total, 5.5% and 1.7% of patients, respectively, discontinued treatment due to an AE.

“We are eagerly awaiting longer-term data to understand the full impact of the results from this trial. It’s encouraging to see that olaparib is consistently delaying the progression of metastatic pancreatic cancer in patients with aBRCAmutation. We’re potentially on the cusp of a new age of treatment for pancreatic cancer, where for the first time we can tailor therapy based on a biomarker and where having aBRCAmutation opens up more treatment options,” said ASCO Expert Suzanne Cole, MD.

References:

1. Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germlineBRCAmutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. Presented at: 2019 ASCO Annual Meeting; Chicago, IL; May 31-June 4, 2019. Abstract LBA4.
2. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for GermlineBRCA-Mutated Metastatic Pancreatic Cancer.N Engl J Med. doi: 10.1056/NEJMoa1903387.
3. AstraZeneca. Lynparza significantly delayed disease progression as 1st-line maintenance treatment in germlineBRCA-mutated metastatic pancreatic cancer. Published February 26, 2019. https://bit.ly/2BSBlHE. Accessed February 26, 2019.