AZ Lynparza Head Hopes 2020 Will See PARP Inhibitor Treating Pancreatic Cancer
Executive Summary
AstraZeneca and Merck & Co hope Lynparza will soon have a third treatment indication after their PARP inhibitor became the first to demonstrate a benefit in germline BRCA-mutated metastatic pancreatic cancer, having hit targets in the Phase III POLO trial.
AstraZeneca PLC and Merck & Co. Inc. will soon initiate talks with regulators after their breast and ovarian cancer drug Lynparza (olaparib) cut the risk of disease progression or death as a first-line maintenance treatment in germline BRCA-mutated metastatic pancreatic cancer. If all goes well the PARP inhibitor will have its third indication in by 2020, according to Greg Rossi, global medicines lead for Lynparza at AstraZeneca.
Positive POLO
He was speaking to Scrip after Lynparza, which is currently being used as treatments for ovarian and breast cancer, showed itself in the Phase III POLO trial to be better at preventing gBRCAm metastatic pancreatic cancer from worsening when compared with a placebo.
"We would hope to have a new use for Lynparza in 2020 [as a treatment for pancreatic cancer]." - AstraZeneca Lynparza global program head Greg Rossi
Topline data from the trial, announced Feb. 25, showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with Lynparza versus placebo. The safety and tolerability profile of Lynparza was consistent with previous trials, the companies said.
Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response in cells/tumors harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2.
"If we in pancreatic cancer show that we’ve got a clinical effect – and as we expand beyond breast and ovarian cancer – it gives us renewed confidence about the potential for this molecule in multiple tumor settings.” - Greg Rossi
Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.
"We thought that the biology associated with DNA damage repair and some of the early data that we had seen in studies gives an indication that at least in BRCA patients there could be benefit from Lynparza,” Rossi explained. Patients with BRCA gene mutation represents between 5% and 7% of pancreatic patients.
Patients in the randomized POLO trial started receiving Lynparza after around 16 weeks of having had platinum chemotherapy.
"We moved patients then to a maintenance treatment with Lynparza, which produced a statistically significant result. The primary endpoint was progression-free survival. We treated the patient until the point of disease progression,” Rossi said.
He did not reveal for how long the patients remained progression-free. That will be revealed with full results of the trial at an undisclosed medical meeting later this year.
“We will now have conversations with regulators over the next few weeks to see if we can get a licensed new use for Lynparza as a treatment for pancreatic cancer," he said in an interview.
Lynparza Looks Set For Pancreatic Cancer Status
"Our typical timelines for a supplemental indication review by regulators is something like a year, perhaps a little less. So, we would hope to have a new use for Lynparza in 2020 [as a treatment for pancreatic cancer]," Rossi.
"There is a very big unmet medical need in pancreatic cancer and the regulators are very aware of that unmet need. We are committed to making this treatment available to pancreatic cancer patients. We will discuss any opportunity to move this quickly,” he added.
Lynparza already leads the PARP inhibitor class across all tumor types with more than 50% total patient share.
Other PARP Inhibitors include Pfizer Inc.'s Talzenna (talazoparib), Clovis Oncology Inc.'s Rubraca (rucaparib) and Tesaro Inc.'s (acquired by GlaxoSmithKline PLCin Dec 2018) Zejula (niraparib).
AstraZeneca's Rossi said results from the POLO trial trial "positions us as the pioneer in pancreatic cancer. We are now the only PARP inhibitor now with poster Phase III data in three independent tumors, those being breast, ovarian and pancreatic."
Other Tumor Types Targeted Too
Lynparza is being tested in a range of PARP-dependent tumor types with defects and dependencies in the DDR.
"We have a pretty broad program for Lynparza. We have ongoing Phase III programs as monotherapy in prostate, but also have a series of combination trials. They include in prostate cancer, ovarian but also in bladder cancer, and in non-small cell lung cancer," Rossi said.
“Our combination experiments will allow us to move into other tumor types so potentially outside of DDR gene mutation groups. So within DNA damage response we’re looking at a series of genes that are highly implicated in DNA damage repair pathways, of which BRCA are an archetypal DNA damage repair gene, but there are a range of other genes that are really interesting and maybe just as important in repairing DNA damage. And we think that Lynparza could easily work in patients that have got mutations in those gene pathways.”
"The takeaway from the POLO trial is that it shows the power of Lynparza."
"If we in pancreatic cancer show that we’ve got a clinical effect – and as we expand beyond breast and ovarian cancer – it gives us renewed confidence about the potential for this molecule in multiple tumor settings,” Rossi concluded.