The FDA has scheduled an Oncologic Drugs Advisory Committee hearing for December 17, 2019, to discuss a supplemental new drug application for olaparib tablets as a maintenance treatment of adult patients with deleterious or suspected deleterious BRCA-mutant metastatic pancreatic adenocarcinoma whose disease has not progressed on frontline platinum-based chemotherapy.
The FDA has scheduled an Oncologic Drugs Advisory Committee hearing for December 17, 2019, to discuss a supplemental new drug application for olaparib (Lynparza) tablets as a maintenance treatment of adult patients with deleterious or suspected deleterious BRCA-mutant metastatic pancreatic adenocarcinoma whose disease has not progressed on frontline platinum-based chemotherapy.1
Recently reported results from the phase III POLO trial showed a progression-free survival (PFS) benefit with olaparib compared with placebo in patients with germline BRCA-mutated metastatic pancreatic cancer. The median PFS with the PARP inhibitor was 7.4 months compared with 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.82; P = .0038).2,3 In addition, after 2 years, 22.1% of patients had no disease progression versus 9.6% of those who received placebo.
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 germline BRCA1 or BRCA2 mutation 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 therapy 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.
Patients who were eligible for enrollment were previously treated for metastatic disease and had not progressed following completion of ≥16 weeks of frontline platinum-based chemotherapy. Additionally, patients had to have a known deleterious or suspected deleterious germline BRCA mutation. 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 had BRCA2 mutations, and the remainder had BRCA1 mutations.
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).
Regarding safety, there were no new safety signals with olaparib. Grade ≥3 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.
Health-related quality of life (HRQoL) findings of the POLO trial were presented during the 2019 ESMO Congress, which showed that there was no difference between arms for global HRQoL.4 The adjusted mean difference for physical function scale did not reach the threshold that was considered to be clinically meaningful, and the global HRQoL and physical function remained moderately stable over time. There was no difference in time to sustained clinically meaningful deterioration (TSCMD) at 21.2 months for olaparib versus 6.0 months for placebo (HR, 0.72; 95% CI 0.41-1.27; P = .25).