The Oncologic Drugs Advisory Committee (ODAC) voted 7 to 5 in favor of recommending the FDA approve olaparib (Lynparza) as a first-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas whose disease has not progressed following frontline platinum-based chemotherapy, according to AstraZeneca and Merck, the developers of the agent.
The FDA granted priority review to the supplemental new drug application (sNDA) for the PARP inhibitor for this indication in August 2019 and set a Prescription Drug User Fee Act (PDUFA) date for the fourth quarter of 2019.
“We are pleased with the ODAC’s recommendation for Lynparza and the potential to bring a personalized, biomarker-targeted medicine to patients with germline BRCA-mutated metastatic pancreatic cancer,” José Baselga, executive vice president, oncology R&D, said in a press release. “Patients with advanced pancreatic cancer historically have faced poor outcomes due to the aggressive nature of the disease and limited treatment advances over the last few decades. We look forward to working with the FDA as it completes the review of our application.”
The sNDA submission was based on results from the phase III POLO trial. The results suggested a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and reduced the risk of disease progression or death by 47% (HR 0.53; 95%CI, 0.35-0.82, P = 0.0038). Moreover, olaparib almost doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death, compared with placebo (median, 7.4 months vs 3.8 months, respectively).
These data were published in The New England Journal of Medicine and presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.
In the multi-center cohort of 154 patients with gBRCA metastatic pancreatic cancer whose disease had not progressed on first-line platinum-based chemotherapy, patients were randomized 3:2 to receive olaparib (300 mg twice daily) or placebo, until disease progression. The primary endpoint was PFS and the key secondary endpoints included overall survival (OS), time to second disease progression, overall response rate, and health-related quality of life.
The benefit of maintenance was seen consistently across end points. In patients with measurable disease at baseline, 23% responded to olaparib versus 12% on placebo (OR, 2.30; 95% CI, 0.89-6.76) and had a median duration of treatment in excess of 2 years (24.9 months; 95% CI, 14.8 to could not be calculated) versus 3.7 months on placebo (95% CI, 2.1 to could not be calculated). OS at interim analysis was 18.9 months on olaparib versus 18.1 months on placebo but did not reach statistical significance (HR, 0.90; P = 0.68).
The most common adverse events (AEs) were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhea (29%), anemia (28%), decreased appetite (25%), and constipation (23%). The most common grade 3 or higher AEs were anemia (11%), fatigue/asthenia (5%) decreased appetite (3%), abdominal pain (2%), vomiting (1%), and arthralgia (1%).
Olaparib is currently under regulatory review in the EU, Canada, and other jurisdictions in addition to the US as a first-line maintenance treatment for patients with gBRCAm metastatic pancreatic cancer.
The PARP inhibitor is currently approved in 65 countries for the maintenance and treatment of platinum-sensitive relapsed ovarian cancer, regardless of BRCA status. It is approved in the US, EU, Japan, and several other countries as a first-line maintenance treatment for BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 44 countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer.
Lynparza recommended by FDA advisory committee for 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer [news release]. Kenilworth, New Jersey. Published December 17, 2019. astrazeneca.com/content/astraz/media-centre/press-releases/2019/lynparza-recommended-by-fda-advisory-committee-for-1st-line-maintenance-treatment-of-germline-brca-mutated-metastatic-pancreatic-cancer.html. Accessed December 18, 2019.