Olaparib Approaches EU Approval for Frontline Maintenance in Pancreatic Cancer

Jose Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZenec

José Baselga, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended olaparib (Lynparza) 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.¹

“Patients with advanced pancreatic cancer have seen limited treatment advances over the last few decades. We are now one step closer to potentially bringing the first targeted medicine to certain biomarker-selected patients with advanced pancreatic cancer in the EU,” José Baselga, MD, PhD, executive vice president, R&D Oncology, AstraZeneca, which codevelops olaparib with Merck (MSD), stated 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.

References

1. LYNPARZA® (olaparib) Receives Positive Opinion from EU CHMP for First-Line Maintenance Treatment of Patients with Germline BRCA-Mutated Metastatic Pancreatic Cancer. Posted June 1, 2020. https://www.mrknewsroom.com/newsroom/news-releases/news-details/2020/LYNPARZA-olaparib-Receives-Positive-Opinion-from-EU-CHMP-for-First-Line-Maintenance-Treatment-of-Patients-with-Germline-BRCA-Mutated-Metastatic-Pancreatic-Cancer/default.aspx. Accessed June 1, 2020.
2. LYNPARZA® (olaparib) Approved by FDA as First-Line Maintenance Treatment of Germline BRCA-Mutated Metastatic Pancreatic Cancer. Merck. Published December 30, 2019. https://bit.ly/2ZDWX4R. Accessed December 30, 2019.
3. 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.
4. 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
5. NDA 208558/Supplement 10 Lynparza (olaparib) tablets AstraZeneca [ODAC briefing document]. FDA. Published December 17, 2019. https://bit.ly/2syDPsI. Accessed December 17, 2019.
6. Lynparza® for the Maintenance Treatment of Patients with Germline BRCA-Mutated Metastatic Adenocarcinoma of the Pancreas [sponsor briefing document]. Published November 13, 2019. https://bit.ly/36Kd2IE. Accessed December 17, 2019.

The CHMP based its recommendation on data from the phase 3 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).^2,3,4,5,6 In addition, after 2 years, 22.1% of patients had no disease progression versus 9.6% of those who received placebo.