A targeted cancer drug from AstraZeneca and Merck & Co. sparked some cautious optimism earlier this year, when the companies revealed it had delayed tumor growth in certain pancreatic cancer patients already on chemotherapy.
Fuller results from the trial, presented Sunday at the American Society of Clinical Oncology’s annual meeting, show why: A typical patient given AstraZeneca and Merck’s Lynparza went nearly twice as long without disease progression compared to those given placebo.
Yet a first look at whether Lynparza lengthened patient lives found no significant difference in overall survival between the two groups. While an interim analysis, the finding highlights the difficulties in addressing pancreatic cancer, known to be particularly hard to treat.
POLO, as the study is called, looked at 154 patients with metastatic pancreatic cancer who have mutations in a gene called BRCA. Researchers believe these mutations increase the risk of developing select cancers — including pancreatic, where an estimated 4% to 7% of patients have them.
Patients whose tumors had not advanced on chemotherapy were given Lynparza in hopes of staving off later tumor growth. After two years, 22% on Lynparza maintenance therapy had no disease progression, compared to less than 10% on placebo. Median progression-free survival, the main objective of the study, was 7.4 months versus 3.8 months, respectively.
«There are people on the study who are now living into their third year,» Suzanne Cole, a medical oncologist at University of Texas Southwestern Medical Center, said in an interview with BioPharma Dive.
«Just the idea of somebody having this incredibly long response and their survival shifting from a 12-month time point to a two-and-a-half-year time point is incredible.»
An interim analysis on survival was conducted after roughly half of the participants in the study died. Median overall survival, or OS, stretched to 18.9 months and 18.1 months in the drug and placebo groups, according to data being published Sunday in the New England Journal of Medicine. A final survival analysis is planned for later.
Investigators noted that OS results could have been affected by the fact that patients in the placebo group whose tumors progressed were subsequently given other therapies during the trial period.
«There are many reasons why you might miss OS in clinical trials, including crossover,» Olivier Nataf, vice president of U.S. oncology at AstraZeneca, told BioPharma Dive.
Nataf added that further study is needed to better understand the effects Lynparza has on BRCA-mutated pancreatic cancer. He said that, moving forward, a focus will be evaluating the drug in patients with less advanced disease, or perhaps in combination with other pharmaceuticals.
POLO additionally found a less than 3-point difference in health-related quality-of-life scores between the Lynparza and placebo groups, as measured by a 100-point scale.
AstraZeneca announced the trial’s success on PFS in late February, but specific data points weren’t made public until the disclosures at ASCO and in NEJM. Quality of life and OS were secondary endpoints in POLO.
Response rates were greater in the Lynparza group. There, 20% of patients experienced some degree of tumor shrinkage — double the 10% seen in the placebo group. Two patients experienced complete responses, both of which were in the Lynparza group and remained ongoing at the time of data cutoff.
Despite drugmakers’ best efforts, new and more effective treatments for pancreatic cancer have been elusive. In the last 12 months alone, therapies from Celgene, Merrimack Pharmaceuticals, and AbbVie and Johnson & Johnson have failed in the clinic.
As a result, long-term PFS and OS remain low in pancreatic cancer. Research cited in the NEJM article indicates that patients treated with standard-of-care first-line therapies typically go six months before their disease advances, and fewer than 10% live longer than five years following diagnosis.
AstraZeneca, along with a handful of other drug developers, are trying to see whether PARP inhibitors, a drug class that includes Lynparza, can extend those timelines.
PARP inhibitors prevent a kind of protein from repairing broken DNA. BRCA mutations effectively do the same, though with a different protein. The thinking is that using a PARP inhibitor in patients who already have BRCA mutations would prevent cancer cells from repairing themselves, thereby causing them to destruct.
But while PARP inhibitors and other targeted cancer therapies have shown promise, it’s worth noting that only a small percentage of patients are eligible to receive them. In POLO, just 7.5% of the 3,315 patients screened had germline BRCA mutations.
«I am still wanting the magic solution for the 95% of people who don’t have the BRCA mutation,» Cole said. «These incremental improvements in this particular slice of the population are fantastic. However, we have to keep finding treatments for the people that are unlucky to not have that mutation that’s driving their cancer.»
Lynparza is one of four PARP inhibitors to have hit the United States market.
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