In posters presented at the 2020 Gastrointestinal Cancers Symposium, POLO investigators reported that health-related quality of life was preserved during maintenance olaparib in patients with BRCA 1/2-positive pancreatic cancer, as evidenced by a low symptom burden over time.1 Other studies described the safety profile of patients treated with olaparib2 and characterized those who experienced early progressive disease in the study.3
POLO evaluated maintenance therapy in patients with pancreatic cancer, testing the benefit of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients with metastatic disease and a germline BRCA1/2 mutation whose disease had not progressed during at least 16 weeks of treatment with first-line platinum-based chemotherapy.4 Maintenance olaparib was associated with a significant progression-free survival benefit vs placebo (hazard ratio = 0.53; P = .004): median of 7.4 months vs 3.8 months.
Health-Related Quality of Life Maintained
Michael J. Hall, MD
Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia, led the analysis of health-related quality of life of patients in the POLO trial. As background, he noted that health-related quality of life is “often poor in metastatic pancreatic cancer because of the high symptom burden, often being associated with fatigue, abdominal pain, appetite and weight loss, and reduced functional status.” Moreover, he added, conventional treatments add more toxicities that compromise health-related quality of life.
The progression-free survival benefit found with maintenance olaparib was achieved without compromising health-related quality of life, as assessed using the European Organisation of Research and Treatment in Cancer Quality-of-Life Questionnaire Core 30-item module (EORTC QLQ-C30). Health-related quality of life was preserved with olaparib; there was no clinically meaningful difference between patients in the olaparib and placebo arms.
The new data reported at this meeting came from the EORTC QLQ-PAN26, which was completed by 147 patients in the trial. This instrument (with a 0- to 100-point scale) comprises 26 questions assessing primarily physical changes and symptoms. Three multiple-item scales were included in the analysis: pancreatic pain, jaundice, and digestive symptoms. A 10-point change from baseline was prespecified as clinically meaningful.
“Health-related quality of life was preserved with olaparib; there was no clinically meaningful difference between patients in the olaparib and placebo arms.”— Michael J. Hall, MD
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The analysis showed no physical changes that were worse than those in the placebo arm, with a suggestion that the time to sustained clinically meaningful deterioration was delayed with maintenance olaparib. Over the first 6 months of treatment, no clinically meaningful differences were observed in adjusted mean change from baseline symptom scores when calculated across the first 6 months of treatment within and between study arms. Furthermore, olaparib appeared to delay the time to sustained clinically meaningful deterioration in the pancreatic pain domain, although it was not statistically significant; the median time to sustained clinically meaningful deterioration was 11 months with olaparib and 8 months with placebo (hazard ratio = 0.81), and the rates of time to sustained clinically meaningful deterioration at 12 months were 47.1% and 29.5%, respectively, Dr. Hall reported.
Safety Profile Described
The safety analysis, presented in another poster, included 151 patients: 91 on the olaparib arm and 60 on the placebo arm.3 The median total treatment duration was more than 50% longer in the olaparib group (6.0 vs 3.7 months, respectively). As treatment increased, most treatment-related side effects did not accumulate.
“In patients with germline BRCA mutation and metastatic pancreatic cancer treated with maintenance olaparib, adverse events of fatigue/asthenia, nausea, diarrhea, anemia, decreased appetite, and vomiting usually occurred early and, with the exception of fatigue/asthenia and diarrhea, did not increase in prevalence over time,” pointed out Michele Reni, MD, of IRCCS Ospedale at San Raffaele Scientific Institute in Milan, Italy.
Michele Reni, MD
Overall, adverse events grade ≥ 3 were observed in 40% of the olaparib group and 23% of the placebo group; four patients treated with olaparib had a grade 4 toxicity. “With the exception of fatigue and asthenia, the median duration of the characterized adverse events was less than 2 months in the olaparib group,” he said. “The majority of cases of fatigue and asthenia were low grade.” Fatigue and asthenia were the only adverse events that led to treatment discontinuation, occurring in two patients. Most side effects could be treated with supportive therapy. Anemia was treated with blood transfusion in 16%.
“At 12 months, 76% of patients still on maintenance olaparib were receiving the recommended dose of 300 mg twice daily,” Dr. Reni said.
“At 12 months, 76% of patients still on maintenance olaparib were receiving the recommended dose of 300 mg twice daily.”— Michele Reni, MD
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Factors Associated With Early Disease Progression
Early disease progression or death (within 4 months of randomization) has previously been observed in between 35% and 45% of patients receiving first-line platinum-based chemotherapy and in 60% receiving sunitinib in the maintenance setting, small studies have shown. “However, the predictive factors for early disease progression are currently unknown, and assessment of early disease progression in the maintenance setting is limited,” noted Teresa Macarulla, MD, of Val d’Hebron University Hospital and Institute of Oncology, Barcelona, first author of the study. “Here, we evaluated baseline factors that might potentially be associated with early disease progression in patients receiving maintenance treatment on the POLO trial.”
The multivariate analysis included data from 127 patients, 56 (44%) of whom were classified as early progressors.2 A lower physical functioning score by patient-reported EORTC QLC-C30 questionnaire, treated as a continuous variable, was the only factor associated with a significantly increased risk of early disease progression (odds ratio = 0.973; P = .023). For this variable, early progressors had a mean score of 81.7, whereas the score for nonprogressors was 86.7, she reported.
Teresa Macarulla, MD
“A clinically meaningful lower baseline score, indicating worse physical functioning, was associated with a significant increase in the risk of early disease progression,” Dr. Macarulla said.
DISCLOSURE: Dr. Hall disclosed financial relationship with Caris Life Sciences, Foundation Medicine, Invitae, Myriad Genetics, and AstraZeneca and shares a patent for a novel method of investigating hereditary colorectal cancer genes. Dr. Reni has received honoraria, consulting fees, or travel expenses from Baxalta/Shire, Celgene, Novartis, Novocure, and Pfizer. Dr. Macarulla has received honoraria, consulting fees, or travel expenses from Serviere, AstraZeneca, Shire, Baxalta, and Celgene.
REFERENCES
1. Hall MJ, Golan T, Hammel P, et al: Pancreatic cancer-specific health-related quality of life with maintenance olaparib in patients with metastatic pancreatic cancer and a germline BRCA mutation: Phase III POLO trial. 2020 Gastrointestinal Cancers Symposium. Abstract 648. Presented January 24, 2020.
2. Reni M, Kindler HL, Hammel P, et al: Adverse events with maintenance olaparib in patients with a germline BRCA mutation and metastatic pancreatic cancer: Phase III POLO trial. 2020 Gastrointestinal Cancers Symposium. Abstract 686. Presented January 24, 2020.
3. Macarulla T, Kindler HL, Hammel P, et al: Early progression in patients with metastatic pancreatic cancer and a germline BRCA mutation: Phase III POLO trial of olaparib vs placebo. 2020 Gastrointestinal Cancers Symposium. Abstract 750. Presented January 24, 2020.
4. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.
