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The final analysis of survival data from the phase III POLO trial of metastatic pancreatic cancer and a germline BRCA mutation found no clinically significant overall survival (OS) benefit for active maintenance olaparib compared with placebo.

Nevertheless, use of the PARP inhibitor for active maintenance was associated with statistically significant improvements in clinically relevant end points relative to placebo, said Hedy L. Kindler, MD, medical director of Gastrointestinal Oncology at the University of Chicago, and colleagues, in their study in the .

These OS benefits included increases in median time to first subsequent cancer therapy or death (hazard ratio [HR] 0.44, 95% CI 0.30-0.66, P<0.0001); time to second subsequent cancer therapy or death (HR 0.61, 95% CI 0.42-0.89, P=0.0111); and time to discontinuation of study treatment or death (HR 0.43, 95% CI 0.29-0.63, P<0.0001).

These findings indicate a durable response to olaparib maintenance in a subset of patients surviving more than 2 years after randomization. Currently, the 5-year survival rate for metastatic pancreatic adenocarcinoma is 3%, with a median progression-free survival (PFS) of 6 months.

The following Q&A discusses the details of the study. (The researchers did not respond to requests for comment, and the answers here are from the text of the report.)

How common are loss of function BRCA1 and BRCA2 mutations in pancreatic cancer?

Estimates of the prevalence of such BRCA mutations among all patients with pancreatic cancer range from 4-8%, with indicating a prevalence of approximately 6%.

What is the goal of active maintenance therapy in patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation?

Active maintenance therapy after cessation of initial treatment aims to extend PFS and overall survival without compromising health-related quality of life. In patients with metastatic pancreatic cancer and a germline BRCA mutation, active maintenance olaparib is recommended in the National Comprehensive Cancer Network clinical guidelines.

What do the results from your final analysis add to the literature?

Our finding that substantially more patients in the olaparib arm than in the placebo arm remained free of subsequent cancer therapy at 3 years is . This extends the time that patients are free from the potentially toxic effects of subsequent chemotherapy.

This is also particularly relevant in terms of extending overall survival in a subset of patients. Patients in the olaparib arm also had a numerically longer time to second disease progression. Although the HR favoring olaparib did not reach clinical significance, it is also clinically meaningful because it suggests preservation of treatment benefits.

How does this final analysis compare with earlier analyses from the POLO trial?

Our primary analysis of progression-free survival, at data cutoff in January 2019, showed a significant PFS benefit for active olaparib maintenance therapy versus placebo (7.4 months vs 3.8 months, respectively). Our interim analysis of OS showed no significant difference between the olaparib and placebo arms, with a median OS of 18.9 months vs 18.1 months. Our preplanned final analysis of OS data from the second data cutoff, on July 21, 2020, showed that the median OS was 19.0 months in the olaparib arm and 19.2 months in the placebo arm (HR 0.83, P=0.3487).

The final analysis of overall survival -- defined as the time from random assignment to death -- was performed after 108 of the 154 randomly assigned patients (70.1%) had died. At the time, 26 patients (28.3%) in the olaparib arm were alive and in follow-up compared with 11 patients (17.7%) in the placebo arm.

The median duration of follow-up was 31.3 months in the olaparib arm and 23.9 months in the placebo arm.

At what point was there a shift in survival data towards a benefit with olaparib maintenance?

The Kaplan-Meier OS curves separated at approximately 24 months, indicative of a subset of long-term survivors in the olaparib arm (37.0% vs 27.4% in the placebo arm). The greatest point of separation in the curves was at 36 months, with survival rates of 33.9% in the olaparib arm and 17.8% in the placebo arm.

Patients in the olaparib arm also remained on study treatment more than three times longer than patients in the placebo arm (25.9 months vs 7.3 months).

The tail on the curve may reflect a distinct biologic subgroup of patients who have a unique deficiency in homologous recombination, and further research is required to explore this .

Was the duration of first-line chemotherapy associated with any survival trends?

Our results do not suggest an effect of the duration of prior platinum therapy on olaparib efficacy. However, our subgroup analyses showed that median OS was longer for patients who had received more than 6 months of first-line chemotherapy (32.5 months with olaparib vs 20.6 months with placebo) than for patients who had received 6 months or less of first-line chemotherapy (17.0 vs 15.0 months, respectively).

What did you conclude from the data on safety and quality of life?

The remains consistent with previous experience in other tumor types. A small group of patients have received olaparib for an extended period of time in the POLO trial; it is therefore reassuring that there were no reports of myelodysplastic syndrome or acute myeloid leukemia in either treatment arm and no new primary malignancies on olaparib.

in patients on olaparib maintenance was also shown to be preserved during the trial.

Read the study here.