The safety and efficacy of maintenance olaparib in patients with BRCA1/2-mutated metastatic pancreatic cancer proved to be consistent irrespective of age, according to results of a subgroup analysis from the pivotal phase 3 POLO trial.
The safety and efficacy of maintenance olaparib (Lynparza) in patients with BRCA1/2-mutated metastatic pancreatic cancer proved to be consistent irrespective of age, according to results of a subgroup analysis from the pivotal phase 3 POLO trial presented during the 2020 ESMO World Congress on Gastrointestinal Cancer.1
Results showed that patients within the study who were at least 65 years old and received olaparib as a maintenance therapy were able to obtain long-term progression-free survival (PFS) and a durable tumor response.2
Specifically, at 1 year, investigators found that 21% of the patients who were at least 65 years old were progression free in the olaparib arm versus 41% in the placebo arm. The same PFS rate was upheld at 2 years at 21% in the olaparib arm versus 0% in the placebo arm. In patients younger than 65 years, 39% of patients in the olaparib arm remained progression free versus 9% in the placebo arm. At 2 years, the rates in the olaparib and placebo arms in this age group were 23% and 9%, respectively.
In the randomized, double-blind, placebo-controlled, phase 3 POLO trial, investigators assessed the efficacy of olaparib as maintenance therapy in 154 patients with metastatic pancreatic cancer harboring a germline BRCA1/2 mutation who had not progressed during first-line platinum-based chemotherapy.
Patients were randomized 3:2 to receive oral olaparib at 300 mg twice daily as maintenance treatment (n = 92) or placebo, also administered twice daily (n = 62). Patients were randomized within 6 weeks following the last chemotherapy dose and olaparib/placebo treatment began 4 to 8 weeks of the last chemotherapy dose. Following randomization, patients had weekly clinical visits for the first 4 weeks of therapy and then every 4 weeks while on treatment.
Seventy-one percent of patients on the olaparib arm had an ECOG performance status of 0 versus 61% of those on the placebo arm. Five percent of patients versus 0% of patients had no evidence of disease at study entry in the olaparib and placebo arms, respectively; and 21% versus 30% of patients were aged 65 years or older, respectively.
The primary end point of the trial was PFS via blinded independent central review, and secondary end points included overall survival, time from randomization to second progression or death, objective response rate, disease control rate, safety, and tolerability.
Previous results published in the New England Journal of Medicine showed a median PFS that proved to be consistent regardless of response to prior platinum-based chemotherapy (complete/partial hazard ratio [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 investigative arm was more than twice of that observed in those on the placebo arm (6-month PFS, 53% vs 23%).3
A subgroup analysis of the trial showed that the treatment had consistent activity across prespecified subgroups, and the HR in patients aged 65 years or older was 1.02 (95% CI, 0.45-0.60). In an effort to better determine the safety and efficacy of maintenance olaparib specifically in patients aged 65 years or older, investigators conducted additional analyses focused on age groups of patients on the trial.
Of the 92 patients who received olaparib, 30% (n = 28) were aged 65 years or older; of the 62 patients on the placebo arm, 21% fell within that age group. Of those aged 65 years or older, 64% on the olaparib arm versus 46% on the placebo arm had an ECOG performance status of 0; of those aged younger than 65 years, 73% and 65% on the olaparib and placebo arms, respectively, had this performance status.
Patients under the age of 65 were found to have a longer median time from diagnosis to randomization than the older patient population. The median time to diagnosis was 6.1 months versus 6.8 months in those aged 65 years or older in the olaparib and placebo arms, respectively; the younger population experienced a median time to diagnosis of 7.3 months compared with 7.1 months in the olaparib and placebo arms, respectively. Notably, no difference in median baseline EORTC QLQ-C30 physical functioning score was observed between the age groups.
At the time of data cutoff, which was January 15, 2019, 11% (n = 3/28) of patients aged older than 65 years compared with 11% (n = 7/64) aged younger than 65 years had received olaparib treatment for at least 2 years.
Additional results from the analysis presented at the 2020 ESMO World Congress on Gastrointestinal Cancer showed that 14% of 28 patients in the older subgroup of patients had a partial response (PR; n = 3) or complete response (CR; n = 1) with maintenance olaparib; in the placebo arm, 23% had a PR. In the subgroup of patients younger than 65 years, 22% of 64 patients who received olaparib had a CR versus 6% of 49 patients who all had PRs.
With regard to safety, just under half (43%) of patients aged 65 years or older who received olaparib reported a grade 3 or higher adverse event (AE) compared with 33% of those who received placebo. In those aged younger than 65 years, 38% versus 21% experienced a grade ≥3 AE on the olaparib and placebo arms, respectively. Notably, AE and health-related quality of life profiles proved to be consistent between the 2 age groups.
Overall, the effectiveness of olaparib as maintenance therapy was not affected by age, according to the investigators; however, the subgroups that were analyzed in this study were small, and baseline characteristics were not determined to be predictive of the efficacy of the agent in patients aged older than 65 years.
In December 2019, the FDA approved the PARP inhibitor for the maintenance treatment of adult patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen, based on earlier findings of the phase 3 POLO study.