ASCO: Can Imfinzi bring immunotherapy to ovarian cancer?

While immunotherapy has transformed the treatment of many cancers, it has failed to make much of an impact in advanced ovarian cancer, and AstraZeneca is hoping to change that.

At ASCO, AZ reported the full data from its DUO-O study of PD-L1 inhibitor Imfinzi (durvalumab) as a combination regimen with its PARP inhibitor Lynparza (olaparib) given on top of standard first-line therapy with chemotherapy and bevacizumab for newly-diagnosed advanced ovarian cancer.

While Lynparza is already used to treat BRCA-positive ovarian cancer, AZ specifically excluded women with BRCA mutations from DUO-O, raising the possibility that use of the drug could be extended into a non-BRCA population.

The top-line result was reported in April, and now oncologists have been able to see the full dataset, headlined by an increase in progression-free survival (PFS) from 19.3 months with standard care to 24.2 months for the combination at this interim analysis.

The risk of disease progression was 37% lower with Imfinzi/Lynparza, with a greater 51% benefit seen in a subset of patients with another type of homologous recombination deficiency (HRD) mutation. In the latter group, PFS came in at just over 37 months. Overall survival data isn’t yet mature.

In the study, patients were treated initially with Imfinzi in combination with chemotherapy and bevacizumab followed by Imfinzi, Lynparza, and bevacizumab as maintenance therapy.

It’s potentially an important finding - while there have been improvements in the treatment of ovarian cancer in the last decade, diagnosis still tends to occur when the disease is already advanced, and patients tend to relapse within a couple of years.

Role of Imfinzi?

The big question thrown up in the results, however, is the role of Imfinzi, given that PD-1/PD-L1 checkpoint inhibitors have until now largely failed to move the needle in advanced ovarian cancer, with failed trials for Roche’s Tecentriq (atezolizumab), Merck & Co’s Keytruda (pembrolizumab), and Bristol-Myers Squibb’s Opdivo (nivolumab).

It’s notable that, in DUO-O, Imfinzi without Lynparza showed no improvement over bevacizumab and chemo on PFS, and unfortunately the trial was not designed with a Lynparza-only maintenance arm that would have allowed a direct comparison with the combination.

With no evidence of direct contribution from the PD-L1, debate has already started over AZ’s likelihood of securing approval for the complex and costly regimen, especially in light of regulatory scrutiny recently over the safety of PARP inhibitors and how widely they should be used beyond BRCA.

Last year, for example, the label for GSK’s PARP Zejula (niraparib) was narrowed to BRCA patients only after the drug was found to have a detrimental effect on long-term survival in the non-BRCA group. And AZ and Lynparza partner Merck & Co just got FDA approval for Lynparza in BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC) only, despite going after an all-comer label, after a recent FDA advisory committee vote.

ASCO’s own take on the data, delivered by official expert Merry Jennifer Markham, is that more research is needed, but the trial “is indeed promising for patients with advanced ovarian cancer.”

Evaluate notes that further data on the role of combined PD-1/PD-L1 and PARP inhibitor therapy as first-line maintenance therapy for advanced ovarian cancer will come from the Keylynk-001 study of Keytruda with Lynparza – due to report later this year – and the ATHENA study of Opdivo and Pharma & Schweiz’ PARP drug Rubraca (rucaparib, originally developed by Clovis Oncology) expected in 2024.