AstraZeneca Adds Imfinzi and Lynparza to Ovarian Cancer Treatment

AstraZeneca’s usage limitation in ovarian cancer has been a stumbling block despite Lynparza being the most widely prescribed PARP inhibitor. Now, despite the challenges of getting its immunotherapy Imfinzi to market, the British pharma is hoping to remove that thorn.

Phase 3 data presented at the 2023 American Society for Clinical Oncology (ASCO) annual meeting showed that adding Lynparza and Imfinzi to the usual regimen of chemotherapy and Avastin reduced the likelihood of development or death by 37% in newly diagnosed individuals with ovarian cancer without BRCA mutations.

AstraZeneca may have trouble convincing the FDA and gaining momentum in the clinic despite the statistically significant victory because of the absence of proof of contribution from Imfinzi, regulatory worries over the application of PARP inhibitors outside BRCA-mutant tumors, and the enormous number of components included in this multidrug regimen.

While researchers await the results of the DUO-O study, the FDA has already authorized Lynparza monotherapy as a maintenance therapy for BRCA-mutant ovarian cancer following a response to first-line chemotherapy. More people with homologous recombination deficit (HRD) mutations will be able to benefit from the Lynparza-Avastin combo. Now, AZ proposes adding Imfinzi to chemotherapy up front, then commencing a maintenance regimen of Imfinzi and Lynparza for DUO-O.

The experiment seems to validate Lynparza’s claims of efficacy. Adding Imfinzi without Lynparza in another part of the DUO-O study did reduce the chance of illness progression or death, but not by a statistically significant amount (13%).

However, it’s hard to determine if Lynparza alone will suffice because there isn’t an independent arm evaluating that regimen without Imfinzi. The 37% progression-free advantage shown with the Imfinzi-Lynparza combination did appear to be higher than the 29% PFS benefit seen with Lynparza in the PAOLA-1 study among a comparable patient cohort. However, comparing results between trials is difficult because of individual differences among trial participants.

Even worse, the Tecentriq/Avastin/chemotherapy set developed by Roche for ovarian cancer also failed in first-line treatment.

AZ’s major focus, with the inclusion of Imfinzi, is to serve close to 50% of the HRD-negative population, which has proven more difficult to treat with PARP inhibitors. The revised treatment plan was less effective for those individuals.

A total of 37% of patients in the DUO-O trial’s Imfinzi-Lynparza arm and control group have mutations in HRDs other than BRCA. The Imfinzi-Lynparza combination achieved a greater, 51% superiority in progression-free survival among those HRD-positive individuals. Despite the researchers’ belief that it is still clinically significant, this suggests that the benefit in HRD-negative individuals was lower than in the entire group (37%).

Carol Aghajanian, M.D. – an investigator of DUO-O – has warned that it may be a while before researchers learn the overall survival rates from DUO-O. She did note that earlier studies with PARP inhibitors gave her hope that this PFS advantage will one day lead to increased lifespans.

However, even if AZ were to somehow succeed in persuading the FDA to grant approval, the fact that it includes such a large number of drugs may make it difficult to access them

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