NEW YORK – A recent cost-effectiveness analysis of the PARP inhibitor olaparib (AstraZeneca/Merck's Lynparza) as a maintenance treatment for BRCA1/2-mutated, metastatic pancreatic cancer may inform risk-sharing agreements in which health plans agree to pay drugmakers for the therapy only when it benefits patients.
According to the analysis, published in the Journal of the National Comprehensive Cancer Network in November, olaparib's economic value to the healthcare system as a maintenance therapy for metastatic pancreatic cancer is highest in settings where it is most likely to delay disease progression, specifically for patients harboring germline BRCA1 mutations and after patients have received more than six months of chemotherapy in the first-line setting.
A year ago, the US Food and Drug Administration approved olaparib as a maintenance treatment for metastatic pancreatic cancer patients with germline BRCA1/2-mutated tumors following initial platinum-based chemotherapy. Regulators in the European Union approved the drug for the same indication this summer. Between 4 percent and 7 percent of metastatic pancreatic cancer patients harbor a germline mutation in these two genes.
While the FDA doesn't consider cost in regulatory decisions, other stakeholders in the healthcare system do, as do other national regulatory and payor bodies. The latest study published in the JNCCN provides benchmarks for payors as they increasingly consider the settings in which to cover expensive precision oncology treatments. The analysis suggests that if oncologists are expected to administer olaparib cost effectively as a maintenance treatment in pancreatic cancer patients, then they may have to consider not only the molecular features of patients' tumors but also certain clinical factors that may make them more likely to see a progression-free survival benefit from the PARP inhibitor compared to placebo.
Study author Lizheng Shi, a professor at the School of Public Health and Tropical Medicine at Tulane University, suggested that this type of analysis could help health plans offset costs by entering into risk-sharing agreements with drugmakers that tie payment for the therapy to patient benefit. AstraZeneca declined to comment for this article.
Risk-sharing agreements are becoming more common around the world between payors and drug developers and are starting to occur in the US as well. A recent analysis found that half of the performance-based risk-sharing agreements in the US involved drugs with cardiometabolic indications.
Shi is also of the view that this type of cost-effectiveness information identifying subgroups that derive the most benefit from treatment cannot be ignored by doctors given the high cost of the drugs.
While payors will take into account analyses like this to determine coverage, this may not be the most pressing consideration for doctors. Physicians must consider individual patients' needs when prescribing a drug like olaparib, said Mark Linthicum, director of scientific communications at the Innovation and Value Initiative, a non-profit that assesses value in healthcare.
"Yes, studies like this have the potential to change and ideally improve coverage of therapies to provide the most value for certain types of treatments, but first we have to ensure that the measures that guide that coverage are capturing what matters," said Linthicum, who was not invovled in the cost-effectiveness study.
For oncologists, a drug's cost and overall value to the healthcare system is important, but Linthicum argued that they should also weigh the value a therapy provides to patients' lives, factoring in how a treatment might improve their daily functioning, sexual relationships, workplace productivity, as well as the impact on caregivers.
To conduct the cost-effectiveness analysis published in JNCCN, the researchers relied on results from the Phase III POLO trial, in which metastatic pancreatic cancer patients on olaparib maintenance treatment had a median progression-free survival of 7.4 months compared to 3.8 months on placebo. They modeled the costs and relative outcomes benefits of giving pancreatic cancer patients olaparib in different scenarios, assuming that when the incremental cost-utility ratio (ICUR) fell below a willingness to pay threshold of $200,000 per quality-adjusted life-year (QALY) gained, the treatment was cost effective.
"Even though [olaparib] is effective, the current price at which it's available in the market is quite high," said Shi. "We did this analysis to find out if it really brings value to patients, providers, and health systems, in general. What we found was that the overall cost-effectiveness was not favorable."
Olaparib's list price is about $120 per tablet. At the recommended dose of two tablets per day, totaling a 300mg dose, the monthly cost amounts to approximately $7,200. The latest analysis included the drug's list price along with costs attributed to a patient's health states, management of adverse events, and end-of-life care. The researchers estimated that the overall cost of treating a metastatic pancreatic cancer patient receiving olaparib maintenance therapy for a year was $138,407.
Based on the fact that the POLO trial showed a progression-free survival advantage for olaparib maintenance treatment over placebo, but not a survival advantage, the researchers estimated that the PARP inhibitor in general added around six months of life (or an additional 0.483 QALYs) at an incremental cost of $128,266 compared with placebo. This amounted to an ICUR of $265,290 per additional QALY gained, above the pre-specified cost-effectiveness threshold $200,000 per QALY gained.
Among all eligible BRCA1/2-mutated, metastatic pancreatic cancer patients, the probability that maintenance olaparib treatment would be cost effectiveness was 55 percent. However, when researchers drilled down into patients' other characteristics, two subgroups emerged that had a higher likelihood of receiving cost-effective olaparib maintenance therapy. Patients with a BRCA1 mutation had a 69 percent probability of receiving cost-effective treatment and patients who had received more than six months of previous chemo treatment had an 80 percent probability.
In the POLO trial, olaparib reduced the risk of progression or death in study participants by 47 percent compared to placebo. However, in patients with BRCA1 mutations, olaparib reduced the risk of progression or death by 60 percent compared to 37 percent in those with BRCA2 mutations. Similarly, olaparib maintenance after having received more than six months of chemo reduced the risk of progression or death by 65 percent.
"The nature of olaparib in preventing disease progression was a major driver of economic outcomes," the authors wrote in the paper.
Although the FDA's approval makes olaparib maintenance therapy available to metastatic pancreatic cancer patients with BRCA1 and BRCA2 germline mutations after six months of platinum chemo, the cost-effective analysis demonstrates the differential economic value of the treatment in subgroups within the overall study population. As such, when doctors prescribe the treatment to metastatic pancreatic cancer patients with BRCA2 mutations, the value to the healthcare system may be lower, according to this study.
The analysis also identified subgroups that were less likely to see a progression-free survival advantage from olaparib, such as those 65 years or older, and found the drug was less likely to be cost effective in these patients.
Such considerations may be particularly important outside the US, in countries where regulatory bodies do consider cost when assessing the relative value of a drug to the healthcare system. For example, the European Commission granted marketing authorization to olaparib in a smaller biomarker-defined prostate cancer population than the FDA, recommending the drug only for patients with BRCA1/2 mutations, in whom the benefit was most pronounced. The FDA had approved the drug more broadly for prostate cancer patients with mutations in a range of genes involved in homologous recombination repair.
The price of the drug itself was a significant factor in the lack of cost-effectiveness demonstrated in the overall base-case scenario in the study. The authors noted that if the daily cost of olaparib were to be cut in half, the ICUR for maintenance olaparib treatment would be lower than the $200,000/QALY cost-effectiveness threshold for the entire POLO study population.
The Trump Administration recently finalized a rule that will peg Medicare prices of certain prescriptions drugs to their prices in other developed nations. Industry observers predict the rule will face legal challenges from groups aiming to thwart its implementation. Still, the authors of this study wrote that the "initiative may lead to a reduction in the price of olaparib and to achieving more favorable economic outcomes."
Meanwhile, the cost-effectiveness analysis did not take into account the price of genetic sequencing, Shi said, which can cost several thousand dollars depending on the test used. In approving olaparib for metastatic pancreatic cancer patients, the FDA also approved Myriad Genetics' BRACAnalysis CDx to identify patients with BRCA1/2 mutations who might benefit from treatment.
The National Comprehensive Cancer Network recommends germline genetic testing for mutations in cancer risk genes, including BRCA1/2, for all pancreatic cancer patients at diagnosis. Shi noted that factoring in the cost of genetic testing could change the outcome of the findings, but he did not elaborate.
Ultimately, given the high price of olaparib, doctors and healthcare systems cannot ignore the cost of achieving the outcomes patients can hope to see on the treatment, in Shi's view. "Doctors need aclear picturein order to provide precision medicine options to patients," Shi explained. "Without this [cost-effectiveness] information, it can be very difficult for the clinician to make medical decisions and choose the individuals that might have the optimal outcome [from this treatment]."
Linthicum, meanwhile, noted that it is important to keep in mind that a patient's value calculation may not align with a healthcare system view of value. "This study, and many like it, defines benefits as a very limited set of clinical factors," Linthicum said. "While clinical measures like progression-free survival and pharmacodynamics are important, and utility adjustments approximate to a degree impacts on quality of life, this in no way captures the value experienced from patients' perspectives."