Olaparib Approved in Europe for BRCA+ Pancreatic Cancer

The European Commission has approved single-agent olaparib (Lynparza) as a maintenance treatment for adult patients with germline BRCA1/2-mutant metastatic pancreatic adenocarcinoma who have not progressed after a minimum of 16 weeks of a frontline platinum-based chemotherapy regimen.¹

The approval is based on findings from the phase 3 POLO trial, which demonstrated that olaparib nearly doubled the median progression-free survival (PFS) compared with 3.8 months with placebo in patients with germline BRCA1/2-mutated metastatic pancreatic cancer, leading to a 47% reduction in the risk of disease progression or death (HR 0.53; 95% CI 0.35-0.81; P = .0035).^2,3

The decision follows a position opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use, which recommended the PARP inhibitor for use in this setting. In December 2019, the FDA approved olaparib 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.

“Today’s approval opens the door to a new era of biomarker-led care for patients with metastatic pancreatic cancer in the [European Union], which has the highest incidence of any region globally,” Hedy L. Kindler, MD, co-principal investigator of POLO trial, and professor of medicine, at University of Chicago Medicine, stated in a press release. “Lynparza now provides clinicians with a targeted, well-tolerated treatment option for patients with germline BRCA-mutated metastatic pancreatic cancer.”

In the randomized, double-blind, placebo-controlled, phase 3 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 2 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 or older (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 or more 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 end point was PFS by blinded independent central review. Secondary end points 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 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 effects occurring in 10% or more 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 or higher 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.

Data from a subgroup analysis of POLO, which were presented at the 2020 ESMO World Congress on Gastrointestinal Cancer, showed that the PARP inhibitor benefited this patient population regardless of age.⁴

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 PFS and a durable tumor response. Twenty-one percent of patients who were at least 65 years old were progression free at 1 year 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 those 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.

“Patients with metastatic pancreatic cancer historically have faced poor outcomes due to the aggressive nature of the disease and few treatment advances have been made over the last few decades. In the POLO trial, Lynparza nearly doubled median progression-free survival versus placebo after first-line chemotherapy for patients with germline BRCA-mutated metastatic pancreatic cancer,” Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca, which co-develops olaparib with Merck. “This approval underscores the importance of testing all patients for germline BRCA mutations at the time of diagnosis to help inform personalized treatment options for patients in the EU.”

References:

1. LYNPARZA® (olaparib) Approved in the EU for Germline BRCA-mutated Metastatic Pancreatic Cancer [news release]: AstraZeneca and Merck. Published July 8, 2020. Accessed July 8, 2020. https://bit.ly/2O7jvGl.
2. Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. Presented at: 2019 ASCO Annual Meeting; Chicago, IL; May 31-June 4, 2019. Abstract LBA4.
3. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. doi: 10.1056/NEJMoa1903387
4. Kindler H, Hammel P, Reni M, et al. Maintenance olaparib in patients aged ≥65 years with germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial. Presented at: 2020 ESMO World Congress on Gastrointestinal Cancer Virtual Meeting; July 1-4, 2020; Virtual. Abstract S-O3.