Johan Maertens, Sharon C A Chen, George R Thompson, Fariba M. Donovan, Aaron Dane, Mike Birch, Corinne Pinder, Jill Bennett, Valerie Ravenna, Omar Marín Fernández, Geoff Ross, Daniela Zinzi, John H Rex, Phase 2b Olorofim Salvage Therapy Study Group, José María Aguado, Barbara D Alexander, Mickaël Aoun, Rohit Bazaz, Roger J. M. Brüggemann, Anke H. W. Bruns, Methee Chayakulkeeree, Karen Cornelissen, Oliver A. Cornely, Lesley Fitton, Jesús Fortún, Aspasia Georgala, Sarah P. Hammond, Christopher H. Heath, Martin Hoenigl, Steven Holland, Royce Johnson, Philipp Koehler, Varun Mehra, Sanjay R. Mehta, Marisa H. Miceli, Catherine Orla Morrissey, Mohamed Moussa, M Hong Nguyen, Luis Ostrosky-Zeichner, David L. Paterson, Thomas F. Patterson, Markus Plate, Galia Rahav, Riina Rautemaa-Richardson, Bart J A Rijnders, Joanna Schaenman, Stefan Schwartz, Shmuel Shoham, Monica K Sikka, Monica A Slavin, Amparo Solé, Andrej Spec, Frank L Van de Veerdonk, Jose A Vazquez, Paul Verweij, Thomas J Walsh, Stephen R. Walsh, Lewis White
BACKGROUND: Olorofim is an antifungal agent with a novel mechanism of action against Aspergillus spp., rare moulds and dimorphic fungi. Preclinical studies reported unidirectional antagonism between olorofim and mould-active azoles (e.g. azoles other than fluconazole) against Aspergillus fumigatus in which the azole reduces the antifungal effect of olorofim. METHODS: To assess the potential clinical impact of this preclinical finding, we compared outcomes of olorofim with and without concomitant azoles from a Phase 2b salvage study in patients with invasive fungal diseases with few or no treatment options. RESULTS: Analyses are limited by the study size but outcomes were similar for olorofim with and without an azole in combination (whether mould-active or not) at Days 42 (the primary study endpoint) and 84 for both Mycoses Study Group-European Organization for Research and Treatment of Cancer (MSG-EORTC) responses and for all-cause mortality in patients with aspergillosis (77 not receiving an azole, 24 receiving an azole in combination), in patients with coccidioidomycosis (11 not receiving an azole, 30 receiving an azole in combination) and in patients with other fungal infections (50 not receiving an azole, 10 receiving an azole in combination). In addition, the rate of drug-induced liver injury was not increased in patients receiving combination with an azole. CONCLUSIONS: Although limited by small numbers of patients for individual fungi, this analysis did not demonstrate a pattern of reduced clinical efficacy or tolerability of olorofim when given in combination with either the mould-active azoles or with fluconazole.Trial registration number. NCT03583164.