Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Abstract

Purpose: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation. Here, we report the final analysis of overall survival (OS) and other secondary end points.

Patients and methods: Patients with a deleterious or suspected deleterious germline BRCA mutation whose disease had not progressed after ≥ 16 weeks of first-line platinum-based chemotherapy were randomly assigned 3:2 to active maintenance olaparib (300 mg twice daily) or placebo. The primary end point was PFS; secondary end points included OS, time to second disease progression or death, time to first and second subsequent cancer therapies or death, time to discontinuation of study treatment or death, and safety and tolerability.

Results: In total, 154 patients were randomly assigned (olaparib, n = 92; placebo, n = 62). No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487). Kaplan-Meier OS curves separated at approximately 24 months, and the estimated 3-year survival after random assignment was 33.9% versus 17.8%, respectively. Median time to first subsequent cancer therapy or death (HR, 0.44; 95% CI, 0.30 to 0.66; P < .0001), time to second subsequent cancer therapy or death (HR, 0.61; 95% CI, 0.42 to 0.89; P = .0111), and time to discontinuation of study treatment or death (HR, 0.43; 95% CI, 0.29 to 0.63; P < .0001) significantly favored olaparib. The HR for second disease progression or death favored olaparib without reaching statistical significance (HR, 0.66; 95% CI, 0.43 to 1.02; P = .0613). Olaparib was well tolerated with no new safety signals.

Conclusion: Although no statistically significant OS benefit was observed, the HR numerically favored olaparib, which also conferred clinically meaningful benefits including increased time off chemotherapy and long-term survival in a subset of patients.

Trial registration: ClinicalTrials.gov NCT02184195.

FIG 1.

Kaplan-Meier estimates for OS. Circles indicate censored observations. DCO, data cutoff; HR, hazard ratio; OS, overall survival.

FIG 2.

Swimmer plot for patients who survived more than 2 years. Each bar represents an individual patient. ^aPatients who received subsequent olaparib and had ongoing olaparib treatment at second data cutoff. OS, overall survival.

FIG 3.

OS subgroup analyses. The central dashed line indicates an HR of 1 (no treatment effect); outer dashed lines indicate 95% CI result in all patients; the size of circles is proportional to the overall number of events. Subgroups in which fewer than five OS events occurred per group were not included in the analysis. The prespecified gemcitabine-cisplatin subgroup included two patients in the olaparib group and three patients in the placebo group; this subgroup did not meet the threshold for inclusion in the subgroup analysis. Patients who received gemcitabine–cisplatin are not included in the others subcategory of the previous chemotherapy subgroup, but are included in the doublet chemotherapy subgroup. Race was determined from patient records. BICR, blinded independent central review; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FOLFIRINOX, folinic acid–fluorouracil-irinotecan-oxaliplatin; gBRCA, germline BRCA; HR, hazard ratio; OS, overall survival; PR, partial response; SD, stable disease.

FIG 4.

Kaplan-Meier estimates for other secondary end points: (A) investigator-assessed PFS, (B) PFS2, (C) TFST, (D) TSST, and (E) TDT. HR, hazard ratio; PFS, progression-free survival; PFS2, second progression-free survival; TDT, time to discontinuation of treatment; TFST, time to first subsequent cancer therapy or death; TSST, time to second subsequent cancer therapy or death.

FIG A1.

Full patient disposition, showing screening, enrollment, random assignment, and patients still receiving study treatment at DCO2 (July 21, 2020). One patient in the placebo arm was found not to have met the eligibility criteria after initiation of trial intervention, and the intervention was discontinued on day 3. After random assignment, one patient in each trial arm was found not to have met the eligibility criteria and both were included in the intention-to-treat efficacy analyses. Because neither patient received a trial intervention, they were not included in the safety analyses. ^aAny reason not specifically recorded. AE, adverse event; DCO, data cutoff; gBRCA, germline BRCA.

FIG A2.

CONSORT diagram showing patient disposition through enrollment, allocation, follow-up, and analysis. AE, adverse event.

FIG A3.

Swimmer plot for all patients, showing the use of subsequent therapy. Each horizontal line represents an individual patient. DCO, data cutoff; PARP, poly(adenosine diphosphate-ribose) polymerase.