Background
POLO. Phase III, double-blind RCT enrolled 154 patients with metastatic pancreatic adenocarcinoma harboring a germline BRCA1 or BRCA2 mutation whose disease had not progressed during ≥16 weeks of first-line platinum-based chemotherapy, randomized 3:2 to maintenance therapy.
Interventions and follow up
Arm A: Maintenance olaparib 300 mg orally twice daily
Arm B: Placebo
Primary endpoint: PFS (by blinded independent review)
mFollow up: 9.1 mo (olaparib) vs 3.8 mo (placebo) at primary; 31.3 vs 23.9 mo at final OS
Arm B: Placebo
Primary endpoint: PFS (by blinded independent review)
mFollow up: 9.1 mo (olaparib) vs 3.8 mo (placebo) at primary; 31.3 vs 23.9 mo at final OS
Results
mPFS (primary): 7.4 mo vs 3.8 mo (arm A vs B); HR 0.53, 95%CI 0.35–0.82; P=.004
mOS (primary analysis): 18.9 mo vs 18.1 mo, P=.68
ORR: 23% vs 12%, OR 2.30; 95%CI 0.89–6.76
Median duration of response: 24.9 mo vs 3.7 mo
Median time to response: 5.4 mo vs 3.6 mo
Final OS (Golan, ASCO 2021): 19.0 mo vs 19.2 mo; HR 0.83; 95%CI 0.56–1.22; P=.3487
3-yr OS: 33.9% vs 17.8%
mPFS2: 16.9 mo vs 9.3 mo; HR 0.66; 95%CI 0.43–1.02; P=.0613
mOS (primary analysis): 18.9 mo vs 18.1 mo, P=.68
ORR: 23% vs 12%, OR 2.30; 95%CI 0.89–6.76
Median duration of response: 24.9 mo vs 3.7 mo
Median time to response: 5.4 mo vs 3.6 mo
Final OS (Golan, ASCO 2021): 19.0 mo vs 19.2 mo; HR 0.83; 95%CI 0.56–1.22; P=.3487
3-yr OS: 33.9% vs 17.8%
mPFS2: 16.9 mo vs 9.3 mo; HR 0.66; 95%CI 0.43–1.02; P=.0613
Adverse events
Overall: Grade≥3 events 40% vs 23% (arm A vs B)
Hematologic: Anemia 27% vs 17%
Constitutional/GI: Fatigue 60% vs 45%, nausea 35% vs 23%, abdominal pain 29% vs 25%, diarrhea 29% vs 15%
Hematologic: Anemia 27% vs 17%
Constitutional/GI: Fatigue 60% vs 45%, nausea 35% vs 23%, abdominal pain 29% vs 25%, diarrhea 29% vs 15%
Conclusions
Maintenance olaparib significantly prolonged PFS versus placebo in germline BRCA-mutated metastatic pancreatic cancer that had not progressed on first-line platinum therapy, without an overall survival benefit.
Key Limitations
No OS benefit; small biomarker-selected population (germline BRCA ~5–7% of pancreatic cancer); PFS gain modest in absolute terms; no quality-of-life detriment but durable benefit confined to a responder subset.
Clinical Context
First positive phase III biomarker-selected (germline BRCA) trial in pancreatic cancer; led to FDA (2019) and EMA approval of maintenance olaparib in this setting. Endorsed in ESMO/ASCO pancreatic guidance and supports germline BRCA testing for all metastatic pancreatic cancer patients.
References