AstraZeneca to face tough FDA scrutiny with Imfinzi-Lynparza combo in ovarian cancer: analyst

Drugmakers often dream about being the sole player in a therapeutic area. But for AstraZeneca, the lack of rival success stories may mean increased regulatory scrutiny for its new treatment proposal for ovarian cancer.

AZ just bagged an ovarian cancer trial win for a combination of PD-L1 inhibitor Imfinzi, Merck-partnered PARP inhibitor Lynparza, chemotherapy and Avastin. Without giving specific data, AZ said the cocktail staved off disease progression versus chemo and Avastin in newly diagnosed high-grade ovarian cancer without BRCA mutations.

AZ said it will share the results with drug regulators. If approved, AZ would be able to offer the first immunotherapy-containing treatment for ovarian cancer. But, that’s a big if, as one analyst sees it.

The DUO-O phase 3 trial win came as a surprise after multiple previous failures for various combinations of anti-PD-1/L1 and PARP agents, including in ovarian cancer. Combine those results with the FDA’s recent scrutiny around the entire PARP class, and an approval may not yet be within reach for AstraZeneca, SVB Securities analyst Daina Graybosch, Ph.D., suggested in a note to clients.

The FDA will likely want to wait for more mature overall survival data from DUO-O, Graybosch wrote in a Thursday note. Lately, the agency has become extra careful about PARP inhibitors, including Lynparza, which have recently had their ovarian cancer labels narrowed after the FDA questioned the potential for long-term detriment to patient survival in some previously treated ovarian cancer patients.

PARP inhibitors such as Lynparza work best in BRCA-mutated cancer. These agents are typically less powerful against tumors with other mutations known as homologous recombination repair deficiency (HRD), and even less so in HRD-negative tumors. For DUO-O, Graybosch said she expects the FDA will dig into patients with other non-BRCA DNA repair mutations to see if they drove the benefit.

Before AZ’s DUO-O success, two other PD-L1 inhibitors—Merck KGaA’s Bavencio and Roche’s Tecentriq—each failed in their first-line ovarian cancer bids. Bavencio flopped when used with chemo, and Roche’s Tecentriq-Avastin-chemo regimen also bit the dust.

Adding Lynparza appears to have moved the needle for AZ. In the DUO-O trial, the Imfinzi-Avastin-chemo combo only showed a numerical improvement in progression-free survival, while the Lynparza-containing regimen chalked up a statistically significant benefit, according to AZ.

Still, the strategy of combining anti-PD-1/L1 with PARP inhibition has a bad track record, including a phase 3 flop for Merck’s Keytruda and Lynparza in prostate cancer.

While Lynparza appears to have proved its worth in DUO-O, Graybosch said questions could also circle around Imfinzi’s contribution to the regimen. The FDA will also take a closer look at PD-L1 subgroups, she said.

AZ will have a tough regulatory case to make because it’s the first PD-(L)1/PARP combo to claim success. But three other phase 3 trials could confirm this strategy in treatment-naïve advanced ovarian cancer this year, Graybosch noted.

GSK’s phase 3 FIRST trial is testing a combination of its PD-1 inhibitor Jemperli, PARP inhibitor Zejula and chemo with or without Avastin. The study includes both BRCA-mutant and non-BRCA-mutant patients, and it’s designed to show if Jemperli can make a difference. However, in a January interview with Fierce Pharma, GSK’s chief commercial officer Luke Miels said he saw a low chance of that study being successful because ovarian cancer is difficult to tackle for immunotherapy.

Similar to AZ’s DUO-O, Merck is running the Keylynk-001 trial in non-BRCA-mutant patients to evaluate Keytruda with or without Lynparza, plus chemo. In that study, Avastin use is up to investigators’ own discretion.

Graybosch said she expects the GSK and Merck studies will be positive in PD-L1-expressing patients.

In addition, Clovis Oncology is running the ATHENO-COMBO trial evaluating the addition of Bristol Myers Squibb’s Opdivo to its PARP inhibitor Rubraca in patients who’ve responded to platinum-based chemo in the first-line maintenance setting.