No OS Benefit for Active Maintenance Treatment with Olaparib Relative to Placebo in Patients with Metastatic Pancreatic Cancer and a Germline BRCA Mutation

POLO is the first randomised phase III study to investigate active maintenance treatment in patients with germline BRCA-mutated metastatic pancreatic cancer who had previously received first-line platinum-based chemotherapy. In final overall survival (OS) analysis, a higher proportion of patients treated with olaparib than placebo remained alive and in follow-up. However, no statistically significant difference in OS between the two arms was demonstrated. Dr. Hedy L. Kindler of the University of Chicago in Chicago, IL, US and colleagues, who published the findings on 14 July 2022 in the Journal of Clinical Oncology, stated that although no statistically significant OS benefit, benefits for multiple other key secondary endpoints were observed with active maintenance olaparib. With a generally well-tolerated safety profile, active maintenance olaparib conferred clinically meaningful benefit to patients, including increased time without chemotherapy and durable response in a subset of patients.

The authors wrote in the study background that for patients with metastatic pancreatic cancer, the 5-year survival rate is 3%. First-line chemotherapies are associated with side effects and have a median progression-free survival (PFS) of only 6 months. In common with breast, ovarian, and prostate cancers, the risk of pancreatic cancer is increased in patients with loss-of-function BRCA1 and BRCA2 mutations. Estimates of the prevalence of BRCA mutations among all patients with pancreatic cancer range from 4% to 8%. As a result of the deficiency in DNA double-strand break repair in cells with deleterious BRCA mutations, patients with BRCA-mutated cancers are sensitive to platinum-based chemotherapy and to PARP inhibitors.

The phase III POLO study investigated the PARP inhibitor olaparib as active maintenance treatment for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation whose disease had not progressed after at least 16 weeks of first-line platinum-based chemotherapy. A significant PFS benefit was demonstrated in POLO for active maintenance olaparib versus placebo with a median PFS by blinded independent central review of 7.4 months versus 3.8 months (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.35 to 0.82; p = 0.004). The incidence of grade 3 or higher adverse events was similar to that observed among patients receiving olaparib for the treatment of other tumour types. 

At the time of the data cut-off (DCO) for the primary PFS analysis on 15 January 2019 (DCO1), an interim OS analysis (OS data maturity 46.1%) showed no significant OS difference between the olaparib and placebo arms with a median OS of 18.9 months versus 18.1 months (HR 0.91, 95% CI 0.56 to 1.46; p = 0.68). In the latest article, the POLO study team reports the results of the preplanned final analysis of OS (OS data maturity 70.1%) and other key secondary endpoints on 21 July 2020 (DCO2).

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 endpoint was PFS. Secondary endpoints included OS, time to second disease progression or death, time to first and second subsequent cancer treatments or death, time to discontinuation of study treatment or death, and safety and tolerability.

In total, 154 patients were randomly assigned, of whom 92 to olaparib and 62 to placebo. No statistically significant OS benefit was observed with median 19.0 versus 19.2 months (HR 0.83, 95% CI 0.56 to 1.22; p = 0.3487). Kaplan-Meier OS curves separated at approximately 24 months, and the estimated 3-year survival after random assignment was 33.9% versus 17.8%.

Median time to first subsequent cancer treatment or death (HR 0.44, 95% CI 0.30 to 0.66; p < 0.0001), time to second subsequent cancer treatment or death (HR 0.61, 95% CI 0.42 to 0.89; p = 0.0111), and time to discontinuation of study treatment or death (HR 0.43, 95% CI 0.29 to 0.63; p < 0.0001) significantly favoured olaparib. The HR for second disease progression or death favoured olaparib without reaching statistical significance (HR 0.66, 95% CI 0.43 to 1.02; p = 0.0613).

Olaparib was well tolerated with no new safety signals. A small group of patients have received olaparib for an extended period of time in the POLO study and there were no reports of myelodysplastic syndrome or acute myeloid leukaemia in either treatment arm, and no new primary malignancies on olaparib. Health-related quality-of-life has also been preserved on active maintenance olaparib.

The authors commented that OS is considered as the most compelling endpoint for demonstrating the clinical benefit of anticancer treatments and it is likely that the POLO study was not adequately powered to detect a statistically significant OS benefit. Although statistically significant OS benefit for olaparib relative to placebo was not observed, Kaplan-Meier OS curves separated from approximately 24 months, and estimated 3-year survival rates were 33.9% for olaparib and 17.8% for placebo. Active maintenance treatment with olaparib confers a significant benefit for multiple clinically relevant endpoints relative to placebo, including increasing time free from subsequent chemotherapy use. The results also indicate a durable response to olaparib in a subset of patients.

The study was supported by AstraZeneca, as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc, Rahway, NJ, US and by a grant from the US National Institutes of Health National Cancer Institute Cancer Center.

Reference

Kindler HL, Hammel P, Reni M, et al. Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer. JCO; Published online 14 July 2022. DOI:10.1200/JCO.21.01604

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