As reported in The New England Journal of Medicine by Talia Golan, MD, of Sheba Medical Center, Tel Aviv University, and colleagues, the phase III POLO trial showed that maintenance treatment with the poly (ADP ribose) polymerase (PARP) inhibitor olaparib improved progression-free survival vs placebo among patients with germline BRCA-mutant metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy.¹

Study Details

In the double-blind trial, 3,315 patients from 119 sites in 12 countries were screened for BRCA-mutant disease, with 247 (7.5%) being found to have a germline mutation. A total of 154 eligible patients were randomly assigned 3:2 between January 2015 and January 2019 to receive oral olaparib maintenance at 300 mg twice daily (n = 92) or placebo (n = 62) until radiographic disease progression on investigator assessment or unacceptable toxicity. No stratification factors were used in randomization. Patients had to have received at least 16 weeks of continuous first-line platinum-based chemotherapy for metastatic disease. Maintenance treatment was initiated at 4 to 8 weeks after the last dose of first-line therapy. The primary endpoint was progression-free survival in the intent-to-treat population, with radiologic disease progression assessed by blinded independent central review according to modified Response Evaluation Criteria in Solid Tumors version 1.1.

Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.

— Talia Golan, MD, and colleagues

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For the olaparib vs placebo groups, the median age was 57 vs 57 years (30% vs 21% ≥ 65 years); 58% vs 50% were male; an Eastern Cooperative Oncology Group performance status was 0 (71% vs 61%) or 1 (27% vs 37%) in all patients with data; germline mutation was BRCA1 in 32% vs 26%, BRCA2 in 67% vs 74%, and both in 1% vs 0%; first-line platinum-based therapy was a -FOLFIRONOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) variant in 86% vs 81%, gemcitabine/cisplatin in 2% vs 5%, and other platinum-based regimens in 11% vs 13%; the median duration of first-line therapy was 5.0 vs 5.1 months, with 66% vs 65% receiving 16 weeks to 6 months of treatment and the remainder receiving more than 6 months; and the best response to first-line therapy was a complete or partial response in 50% vs 48% and stable disease in the remainder.

Progression-Free Survival

The progression-free analysis was performed after occurrence of disease progression or death in 104 patients. At the time of data cutoff in January 2019, 30 patients who received olaparib and 8 patients who received placebo were still receiving study treatment. The median follow-up for disease progression in patients with censored data was 9.1 months in the olaparib group and 3.8 months in the placebo group.

Median progression-free survival was 7.4 months in the olaparib group vs 3.8 months in the placebo group (hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.35–0.82, P = .004). Progression-free survival rates were 53.0% vs 23.0% at 6 months, 33.7% vs 14.5% at 12 months, 27.6% vs 9.6% at 18 months, and 22.1% vs 9.6% at 24 months.

Hazard ratios for progression-free survival favored olaparib in nearly all subgroups examined. Hazard ratios were as follows: 0.54 (95% CI = 0.35–0.84) in patients who received FOLFIRINOX variants and 0.76 (95% CI = 0.27–2.32) in those who received other regimens; 0.69 (95% CI = 0.43–1.12) in those who received 16 weeks to 6 months of first-line treatment prior to randomization and 0.35 (95% CI = 0.17–0.72) in those who received more than 6 months of first-line treatment prior to randomization; 0.62 (95% CI = 0.35–1.12) in those with a complete or partial response to first-line treatment and 0.50 (95% CI = 0.29–0.87) in those with stable disease; 0.40 (95% CI = 0.20–0.85) in those with BRCA1 mutation and 0.63 (95% CI = 0.39–1.02) in those with BRCA2 mutation; 0.45 (95% CI = 0.28–0.72) in those up to age 65 and 1.02 (95% CI = 0.45–2.60) in those 65 years of age or older; and 0.46 (95% CI = 0.27–0.80) in male and 0.66 (95% CI = 0.37–1.19) in female patients.

A planned interim analysis of overall survival at data maturity of 46% showed no significant difference between the groups (median = 18.9 months vs 18.1 months, HR = 0.91, 95% CI = 0.56–1.46, P = .68).

Adverse Events and Quality-of-Life Assessment

The most common adverse events of any grade in the olaparib group were fatigue/asthenia (60% vs 35% in placebo group), nausea (45% vs 23%), abdominal pain (29% vs 25%), diarrhea (29% vs 15%), and anemia (27% vs 17%). Grade ≥ 3 adverse events occurred in 40% vs 23% of patients, with the most common adverse event in the olaparib group including anemia (11% vs 3%) and fatigue/asthenia (5% vs 2%). Serious adverse events occurred in 24% vs 15% of patients. Adverse events led to treatment interruption in 35% vs 5%, dose reduction in 16% vs 3%, and treatment discontinuation in 5% vs 2%. No cases of myelodysplastic syndrome or acute myeloid leukemia were observed in either group.

Assessment of health-related quality of life with the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire showed no significant or clinically meaningful difference between the olaparib vs placebo groups in change from baseline in global quality-of-life score (between-group difference = –2.47 points on 100-point scale, 95% CI = –7.27 to 2.33).

The investigators concluded: “Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.”

The study was funded by AstraZeneca, as part of an alliance between AstraZeneca and Merck Sharp & Dohme, and by a grant from the National Cancer Institute. ■

DISCLOSURE: Dr. Golan has received honoraria from Merck Sharp & Dohme and Rafael Pharmaceuticals; has served as a consultant or advisor for AbbVie and AstraZeneca; and has received institutional research funding from AstraZeneca and Merck Sharp & Dohme Oncology. For full disclosures of the other study authors, visit www.nejm.org.

REFERENCE

1. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.