Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial

Abstract

Introduction: Current standard-of-care first-line treatments for metastatic pancreatic cancer (mPC) are associated with median progression-free survival (PFS) of approximately 6months; the unmet need for effective and tolerable treatments in this setting is high.Maintenance treatments, used inmany cancers to extend PFS by prolongation of tumour control, are novel inmPC. In a Phase II trial, the PARP inhibitor olaparib demonstrated an objective response rate (ORR) of 21.7%inmPC patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) (Kaufman 2015). POLO (NCT02184195), the first Phase III trial to evaluate the efficacy of maintenance PARP inhibitor treatment in pancreatic cancer, demonstrated a statistically significant and clinicallymeaningful improvement in PFS frommaintenance olaparib versus placebo for patients with a gBRCAmandmPC,whose disease had not progressed during PBC (median 7.4 vs. 3.8 months; hazard ratio 0.53; 95% CI 0.35-0.82; P= .004). At 2 years, 22.1%of olaparib-arm versus 9.6%of placebo-armpatientswere progression free. At an interimoverall survival analysis 46%maturity, the hazard ratio was 0.91 (95%CI 0.56-1.46; P= .68). Safety was consistent with the known profile for olaparib (Golan 2019). Methods: POLO is an international, randomized, double-blind, placebo-controlled trial of patients with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for mPC without progression. There was no limit to duration of chemotherapy. Patients were randomized 3:2 to maintenance olaparib tablets (300 mg bid) or placebo. Treatment began 4-8 weeks after the last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint was PFS by blinded independent central review (BICR; modified RECIST 1.1). Objective response was also assessed by BICR. Results: The ORR among patients with measurable disease at baseline was 23.1% (18/ 78) in the olaparib arm, and 11.5% (6/52) in the placebo arm (odds ratio 2.30; 95% CI 0.89-6.76; P=.103). In the full intention-to-treat population, 18 olaparib-arm (19.6%) and six placebo-arm patients (9.7%) achieved a response. Two olaparib-arm patients (2.2%) achieved a complete response on study treatment; one had a partial response to first-line chemotherapy whereas the other had stable disease. Median duration of response was 24.9 and 3.7 months in the olaparib and placebo groups, respectively; median time to response was 5.4 months and 3.6 months, respectively. 45 (48.9%) olaparib-arm and 34 (54.8%) placebo-arm patients had stable disease for ≥7 weeks. Five olaparib-arm patients (5.4%) who entered the study with no evidence of disease at baseline continued to have no evidence of disease. At 16 weeks the disease control rate (defined as the proportion of patients with a response, or≥15 weeks of stable or no evidence of disease) was 53.3% versus 37.1% in the olaparib and placebo arms, respectively. Conclusion: Patients with a gBRCAm and mPC whose disease had not progressed on PBC derived a statistically significant and clinically meaningful PFS benefit from maintenance olaparib. Olaparib-arm patients were more likely to maintain disease control or achieve a response than those in the placebo arm, and responses were durable lasting a median of more than 2 years.