A role for immuno-oncology in ovarian cancer at last?
Astra’s Duo-O trial suggests that excluding Brca-positive patients could be the key to Imfinzi’s apparent success in ovarian cancer.
Jacob Plieth
3 June, 2023
Astrazeneca appears to have teased out a positive result for Imfinzi in ovarian cancer – a setting that so far has proved intractable for anti-PD-(L)1 drugs. The data, toplined positive in April, concern the Duo-O study of an Avastin/Imfinzi/Lynparza triplet, and have just been presented at an Asco late-breaker.
The result is notable for having apparently succeeded where other PD-(L)1/Parp inhibitor combinations have failed, and one reason for this might be Astra’s exclusion of Brca-positive patients, who would normally be expected to do well on Avastin/Lynparza alone. Still, questions will remain about Imfinzi's contribution, the breadth of the effect, and the robustness of a progression-free survival endpoint.
Debate continues about the validity of PFS in ovarian cancer, and there have been cases where a clinical benefit on PFS has been followed by a clearly negative result in terms of overall survival. This has, for instance, seen use of GSK’s Parp inhibitor, Zejula, narrowed in ovarian cancer maintenance.
Complexities
Duo-O had a complex three-arm design, and included two settings. Active cohorts comprised chemo/Avastin/Imfinzi first line followed by Avastin/Imfinzi with or without Lynparza in the maintenance setting; this was compared against a control cohort of chemo/Avastin followed by Avastin maintenance.
A further crucial twist is that the trial enrolled Brca-negative patients only, and its PFS endpoint was split between two co-primaries: an effect in all-comers, and in Brca-negatives who were nevertheless positive for some other type of HRD mutation.
The good news is that the Avastin/Imfinzi/Lynparza maintenance triplet met both co-primaries, with p<0.0001. The bad that Avastin/Imfinzi had no advantage over control at all.
The survival curves reveal another nuance. It might have been assumed that HRD-positive patients are driving the all-comers benefit, but in fact in HRD-negatives, some 60% of the Duo-O Brca-negative population, the triplet also beat control.
That Parp inhibition should work in patients with no HRD mutation seems counterintuitive. Presenting Duo-O at a pre-Asco press briefing, Memorial Sloan Kettering’s Dr Carol Aghajanian suggested that these patients might not be HRD-negative at all, since the tests on which their HRD status was based “are imperfect”.
Understanding the extent to which HRD-positives are actually responsible for any benefit is key to estimating the possible breadth of any label here. And of course nothing is yet known about OS, a secondary Duo-O endpoint that is still immature.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
Whether Imfinzi is active here goes to the heart of why Duo-O’s positive hit is unexpected. Immunotherapy has tended not to work in ovarian cancer: witness the failures of Roche’s Imagyn-050, Merck KGaA/Pfizer’s Javelin Ovarian 100 and Merck & Co’s Keynote-100 trials.
Next to test the theory will be Merck & Co’s Keylynk-001 trial, which tests Keytruda followed by Lynparza in the maintenance phase, and like Duo-O enrolled only Brca-negative patients. The Athena-Combo trial of Opdivo and Rubraca was to have read out in the first quarter, but its sponsor, Clovis, has gone out of business.
