Olaparib delays progression in BRCA-mutated metastatic pancreatic cancer
Patients with metastatic pancreatic cancer who carry a germline BRCA1/2 mutation may have their risk of disease progression almost halved with olaparib maintenance therapy following first-line treatment with platinum-based chemotherapy, according to results of the phase III POLO trial reported at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.
In the trial, conducted in 154 patients with complete response (CR), partial response (PR) or stable disease (SD) after ≥16 weeks of first-line platinum-based chemotherapy for metastatic pancreatic cancer, median progression-free survival (PFS) was 7.4 months in the olaparib group (n=92) vs 3.8 months in the placebo group (n=62) (hazard ratio [HR], 0.53; 95 percent confidence interval [CI], 0.35 to 0.82; p=0.0038). [Kindler HL, et al, ASCO 2019, abstract LBA4; N Engl J Med 2019, doi: 10.1056/NEJMoa1903387]
“From 6 months onwards, PFS rates more than doubled with olaparib vs placebo,” said lead study author Professor Hedy L. Kindler of the University of Chicago in Chicago, Illinois, US.
At the prespecified time points of 6, 12, 18 and 24 months, PFS rates for olaparib vs placebo were 53 percent vs 23 percent, 33.7 percent vs 14.5 percent, 27.6 percent vs 9.6 percent, and 22.1 percent vs 9.6 percent, respectively.
“Prespecified subgroup analyses of PFS demonstrated consistent benefit of olaparib, including in patients who achieved CR or PR [HR, 0.62; 95 percent CI, 0.35 to 1.12] and those with SD [HR, 0.50; 95 percent CI, 0.29 to 0.87] after first-line platinum-based chemotherapy,” said Kindler.
Median time to second progression (PFS2), defined as time from randomization to progression on second-line treatment, was 13.2 months in the olaparib group vs 9.2 months in the placebo group (HR, 0.76; 95 percent CI, 0.46 to 1.23; p=0.26) when analyzed at 46 percent data maturity.
“PFS2 may indicate the durability of treatment benefit beyond disease progression,” Kindler explained.
“What’s truly remarkable is the median duration of response in the olaparib group, which was 24.9 months, compared with 3.7 months in the placebo group,” she said. “The objective response rate [ORR] was 23.1 percent with olaparib vs 11.5 percent with placebo, with two olaparib recipients achieving CR that was ongoing at the time of data cut-off. The median time to onset of response was 5.4 months vs 3.6 months.”
Overall survival (OS) was not significantly different between the olaparib and placebo groups (median, 18.9 months vs 18.1 months; HR, 0.91; 95 percent CI, 0.56 to 1.46; p=0.68) at a planned interim analysis with 46 percent data maturity.
In the POLO trial, patients with deleterious or suspected deleterious germline BRCA1/2 mutation with no disease progression following ≥16 weeks of first-line platinum-based chemotherapy for metastatic pancreatic cancer were randomized 3:2 to receive maintenance treatment with olaparib 300 mg BID tablets or placebo, starting 4–8 weeks after the last dose of first-line chemotherapy. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included PFS2, ORR, OS, health-related quality of life [HRQoL], and safety and tolerability.
“The study population was a subset of a small subset of patients [ie, 4.6 percent of those screened],” said invited discussant Professor Wells Messersmith of the University of Colorado Cancer Center, Aurora, Colorado, US. “A total of 3,315 patients were screened to identify 247 patients for the study. However, 93 patients [38 percent] with germline BRCA mutation were excluded because they had disease progression, were ineligible for the study, or declined randomization.”
At baseline, patient characteristics were well balanced between the two groups. Most patients had a BRCA2 mutation (67.4 percent in the olaparib group vs 74.2 percent in the placebo group) and an ECOG performance status of 0 (70.7 percent vs 61.3 percent). Prior to chemotherapy, the most common site of metastasis was the liver (66.3 percent vs 77.4 percent).
The median duration of first-line platinum-based chemotherapy was 5 months, with most patients receiving FOLFIRINOX variants (85.9 percent vs 80.6 percent) and just a few receiving gemcitabine/cisplatin (2.2 percent vs 4.8 percent). About half of the patients achieved CR/PR to first-line chemotherapy, and most patients still had measurable disease at baseline (84.8 percent vs 83.9 percent).
Safety and tolerability
“In the trial, olaparib maintenance therapy was well tolerated, with a toxicity profile similar to that seen in other tumour types,” said Kindler.
Grade ≥3 adverse events (AEs) occurred in 40 percent of patients in the olaparib group vs 23 percent of patients in the placebo group, with 5 percent vs 2 percent of patients discontinuing treatment due to an AE. The most common grade ≥3 AEs were anaemia (11 percent vs 3 percent) and fatigue (5 percent vs 2 percent). The median duration of treatment was 6 months in the olaparib group vs 3.7 months in the placebo group.
“Patients’ overall HRQoL was preserved over time, with no significant difference found between the two groups,” added Kindler.
Impact on clinical practice
“Our results, from the first phase III trial to validate a targeted therapy in a biomarker-selected population of pancreatic cancer patients, highlight the importance of germline BRCA mutation testing in this setting,” said Kindler.
“The strategic approach of first-line platinum-based chemotherapy followed by maintenance olaparib should become the new standard of care for patients with metastatic pancreatic cancer with a germline BRCA mutation,” she concluded.
“The effect size for PFS is impressive, especially in the setting of pancreatic cancer,” commented Messersmith. “However, the results showed no OS benefit despite modest rates of subsequent treatment with a PARP inhibitor [1.1 percent in the olaparib group vs 14.5 percent in the placebo group].”
“Furthermore, the placebo-based design is questionable because most oncologists continue first-line therapy indefinitely,” he added. “The trial also did not answer the question of how patients with somatic BRCA mutations should be treated.”
“While germline BRCA mutation testing should be a standard practice for advanced pancreatic cancer, it is unclear how maintenance olaparib compares with the approach of continued treatment with FOLFIRINOX or other platinum-based therapies,” he pointed out. “Given the risk of financial toxicity with the use of PARP inhibitors in this context, maintenance olaparib can be an option for patients with germline BRCA mutations.”