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.

HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line

“…Although mutations of BRCA1/2 in PDAC are associated with increased survival due to a higher susceptibility to platinum-based chemotherapy ( 45 , 46 ), this observation could not be confirmed for HROP68, harboring a BRCA1 mutation. While BRCA -mutated ovarian cancers respond well to the inhibitors of the poly-ADP ribose (PARPi), the PARPi olaparib improved progression-free survival in metastatic PDAC patients with a germline BRCA mutation but failed to improve overall survival ( 47 , 48 ). In our study, olaparib had an inhibitory effect on HROP68Tu2 cells in vitro .…”

Germline BRCA2 variants in advanced pancreatic acinar cell carcinoma: A case report and review of literature

“…The use of PARPi in PACC patients with germline BRCA1 or BRCA2 PV/LPV is anecdotal[ 2 , 23 , 26 ]. Furthermore, the updated analysis of the POLO trial showed a lack of OS benefit and quality of life improvement in their Olaparib-treated patients compared to the placebo arm[ 39 ]. Despite the aforementioned, we believe that metastatic PACC patients with confirmed HRD phenotype and demonstrated strictly defined platinum sensitivity that involved exceptional response after 16 wk of chemotherapy should be considered for the benefit of PARPi, as the case described.…”

Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma

“…This insight led to the design of the POLO trial, where maintenance olaparib versus placebo was studied in patients with PDAC with deleterious germline BRCA1 or BRCA2 mutations who had no evidence of disease progression following at least 16 weeks of platinum-based chemotherapy. The trial met its primary endpoint of improving PFS (7.4 months versus 3.8 months, olaparib versus placebo), but did not demonstrate a statistically significant improvement in OS [ 43 , 44 ]. On the basis of the POLO trial, the FDA approved maintenance olaparib in PDAC patients with germline BRCA mutations.…”