Maintenance olaparib in patients aged >= 65 years with a germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial

In the phase III POLO trial, maintenance olaparib provided a statistically significant and clinically meaningful improvement in progression-free survival (PFS), versus placebo, in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) whose disease had not progressed during first-line platinum-based chemotherapy. While a subgroup analysis showed consistency of treatment effect across prespecified groups, the hazard ratio in patients aged ≥65 years was 1.02 (95% confidence interval 0.45–2.60; Golan NEJM 2019). We performed additional analyses by age group to better determine the efficacy and safety of olaparib in patients aged ≥65 years. Following ≥16 weeks of first-line platinum-based chemotherapy without progression, patients were randomized to maintenance olaparib (tablets; 300 mg bid) or placebo until investigator-assessed disease progression or unacceptable toxicity. PFS (analysed using Kaplan‒Meier method) and response were assessed by blinded independent central review using modified RECIST v1.1. Of 92 olaparib-arm patients, 28 (30%) were aged ≥65, versus 13/62 (21%) placebo-arm patients. Fewer older patients had ECOG performance status 0 (≥65: 64% olaparib versus 46% placebo; <65: 73% versus 65%, respectively), median time from diagnosis to randomization was shorter (≥65: 6.1 versus 6.8 months; <65: 7.3 versus 7.1) and all patients aged ≥65 were Caucasian (<65: 84% versus 94%); however, there was no difference in median baseline EORTC QLQ-C30 physical functioning score between age groups (≥65: 87 versus 80; <65: 87 versus 87; scale 0–100, higher score represents higher functioning). At the data cut-off (15 January 2019) 3/28 patients (11%) aged ≥65 versus 7/64 (11%) aged <65 had received olaparib for ≥2 years. At 1 year, 21% of olaparib-arm versus 41% of placebo-arm patients aged ≥65 were progression-free (<65: 39% versus 9%), and at 2 years, 21% of olaparib-arm versus 0% of placebo-arm patients remained progression-free (<65: 23% versus 9%); however, between-group comparisons may be impacted by small subgroups. 4/28 patients (14%) aged ≥65 had a partial (PR; n=3) or complete (CR; n=1) response to maintenance olaparib versus 3/13 (23%, all PR) in the placebo arm (<65: 14/64 [22%, 1 CR] versus 3/49 [6%, all PR]). Among responders aged ≥65, duration of first-line chemotherapy was 3.7–5.6 months and baseline characteristics were consistent with those of younger responders; the complete responder aged ≥65 had metastatic lung disease and had received 5.6 months of first-line chemotherapy. At the data cut-off, response duration among older patients was 10.2–32.2 months, and 3/4 were ongoing. 43% of olaparib-treated patients aged ≥65 experienced a grade ≥3 adverse event versus 33% of placebo-arm patients (<65: 38% vs 21%). Adverse-event and health-related quality of life profiles were consistent between the two age groups. Patient age did not appear to impact efficacy of maintenance olaparib, although subgroups were small, and as in the overall population, no baseline characteristics were predictive of olaparib efficacy in patients aged ≥65 years. The safety profile of olaparib was consistent irrespective of age. Patients aged ≥65 years with a gBRCAm and metastatic pancreatic cancer can derive long-term PFS benefit (≥2 years) and durable tumour response from maintenance olaparib treatment.