AstraZeneca, Merck's star PARP inhibitor Lynparza expands reach in ovarian cancer with new US approval
Weeks after GSK widened the market for PARP inhibitor Zejula in patients with ovarian cancer, rival AstraZeneca’s market-leading Lynparza has also secured expanded use in women with the disease.
Lynparza, in combination with Roche’s Avastin, has been approved by the FDA for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who have experienced a complete or partial response to first-line platinum-based chemotherapy and whose disease is associated with homologous recombination deficiency (HRD) positive status, defined by either a BRCA mutation and/or genomic instability. Roughly one in two women with advanced ovarian cancer has an HRD+ tumor.
Although drug developers have largely leaned on BRCA mutations to identify patients who can benefit from PARP inhibitors, scientists have suggested that defects in other genes involved in DNA repair — which render cells cancerous — could be prime targets too.
The new Lynparza approval is based on the late-stage PAOLA-1 trial, which showed the addition of the PARP inhibitor to Avastin therapy reduced the risk of disease progression or death by 67%, and that the combination improved progression-free survival (PFS) to a median of 37.2 months versus 17.7 months in patients with HRD positive advanced ovarian cancer who were only given Avastin.
“We expect gradual uptake in the HRD+ setting, as genetic sequencing becomes more integrated into treatment paradigms. Beyond the HRD+ indication, the PARP class may be more challenged given the superior efficacy of Avastin in these patients. However, Avastin usage requires intravenous administration and is associated with a number of side effects that may make oral PARP usage more desirable, especially in the COVID environment,” SVB Leerink analysts said.
The approval will also secure for AstraZeneca $100 million in collaboration revenue from partner Merck.
Akin to Lynparza, GSK’s Zejula and Clovis’ Rubraca are poly ADP-ribose polymerase (PARP) inhibitors. PARP is a protein used by damaged cells to initiate repair, and by thwarting it, the class of drugs is engineered to prevent cancer cells from repairing themselves, thereby catalyzing their destruction.
Last October, Zejula was approved for use in ovarian cancer patients with HRD+ tumors who have been through (and were sensitive to) at least three rounds of chemotherapy. But in late April, Zejula’s use was expanded — on the basis of the PRIMA trial — to women with ovarian cancer who experienced a complete or partial response to first-line platinum-based chemotherapy — accounting for approximately 80% of all ovarian cancer patients — this approval included including HRD negative patients.
“While this does open the door for Zejula to be the only PARP that has formal approval for use in 1L ovarian cancer patients without a marker of repair deficiency (HRD-), the drug may face commercial challenges in this HRD- group, given Avastin monotherapy maintenance demonstrated ~2x the efficacy of PARP monotherapy maintenance based on a comparison between PAOLA-1 and PRIMA trial results,” SVB Leerink analysts wrote in a note.
“We think some clinicians may be reluctant to administer a PARP without determining HRD status given that about 2/3 of non-BRCA+ patients, the HRD- cohort, may get less efficacy with a PARP than with Avastin.”
As the second-to-market drug in the class, Zejula generated ~25% of the revenue Lynparza did last year — £229 million versus £921 million.
Next up on the docket for AstraZeneca and Merck’s Lynparza is an approval for a subset of patients with metastatic castration-resistant prostate cancer, after the companies reported a statistically significant improvement in overall survival.