Olaparib has received an orphan drug designation in Japan for the maintenance treatment of germline BRCA-mutated curatively unresectable pancreatic cancer.
José Baselga, MD, PhD
Olaparib (Lynparza) has received an orphan drug designation in Japan for the maintenance treatment of germline BRCA-mutated curatively unresectable pancreatic cancer, according to AstraZeneca and Merck (MSD), the codevelopers of the PARP inhibitor.1
The designation, which will expedite the development and review of olaparib in Japan for this indication, is based on data from the phase III POLO trial, which showed a progression-free survival (PFS) benefit with olaparib compared with placebo in this setting. The median PFS with the PARP inhibitor was 7.4 months compared with 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.81; P = .0035).2,3 In addition, after 2 years, 22.1% of patients had no disease progression versus 9.6% of those who received placebo.
“Japan has the fifth-highest incidence of pancreatic cancer worldwide and patients have seen limited treatment advances over the last few decades. This designation is an important step forward in bringing the first targeted medicine to biomarker-selected patients with advanced pancreatic cancer in Japan,” José Baselga, MD, PhD, executive vice president, R&D Oncology, AstraZeneca, said in a press release.
In the randomized, double-blind, placebo-controlled, phase III POLO 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.
Some characteristics differed between the two arms, such as ECOG performance status of 0 (71% with olaparib vs 61% with placebo), no evidence of disease at study entry (5% vs 0%, respectively), and ages ≥65 years (21% vs 30%), as well as missing data for baseline disease burden (1% vs 6%).
The median duration of therapy was 6 months for those taking olaparib and 3.7 months for people who received 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 (PFS2), 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%).
Additional results showed that the ORR was 23.1% with olaparib compared with 11.5% in the placebo arm (odds ratio, 2.30); 11.1% (n = 2) of patients on olaparib achieved a complete response compared with 0 on placebo. 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 with a median OS of 18.9 months with olaparib and 18.1 months with placebo (HR, 0.91; 95% CI, 0.56-1.46; P = .68). A final event-driven OS analysis is expected to occur in 2020 once 106 deaths have occurred out of 154 patients. Eighty-four deaths have occurred as of October 27, 2019.
Additionally, olaparib extended the chemotherapy-free interval and delayed time to first subsequent therapy (TFST). While TFST data were 68% mature, results showed that the median TFST was 8.6 months with olaparib compared with 5.7 months for placebo, which was determined to be clinically meaningful (HR, 0.50;  P = .0013).
At the January 15, 2019 data cutoff date, 30% of patients on the olaparib arm remained on treatment compared with 12.9% who were on placebo and were not eligible for subsequent chemotherapy. A total 48.9% and 74.2% on olaparib and placebo, respectively, received subsequent therapy.
The DCR was 53.3% with olaparib versus 37.1% with placebo, and PFS2, which was at 46% maturity, suggested a trend favoring olaparib at 13.2 months versus 9.2 months, respectively (HR, 0.76; 95% CI, 0.46-1.23; P = .26).
Adverse events occurring in ≥10% of patients receiving olaparib included fatigue/asthenia (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).
The most frequent grade ≥3 AEs on the olaparib arm were anemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). AE-related dose interruptions occurred in 35% of the olaparib arm, with AE-related dose reductions occurring in 17% of this cohort. Six percent of the olaparib arm discontinued treatment due to AEs.