The early years of his reign as Grand Master were marked by numerous disputes and quarrels between the Order and Bishop of Malta Martín Royas de Portalrubio over the latter's ecclesiastical jurisdiction.

These disputes were unprecedented in the history of the Order since it had arrived in Malta in 1530 with a grant of virtual sovereignty from Emperor Charles V. La Cassière was unable to resolve the matter, which was finally submitted to Pope Gregory XIII who in turn appointed Pietro Dusina as Inquisitor, a step that La Cassière initially supported but later ended up causing resentment within the Order.

[1] A second major conflict arose in 1575 with the Republic of Venice, when Hospitaller galleys seized a Venetian ship that carried goods for Jewish owners.

The third and most serious cause of discord within the Order during La Cassière's rule was triggered by King Philip II of Spain who managed to arrange the appointment of one of his close relatives, 17-year-old Archduke Wenzel (Wenceslaus) of Austria (son of Emperor Maximilan II, Philip's cousin), to the Grand Priory of Castile and Leon and the Bailiwick of Lora.

These events further fuelled resentment within the Order and the General Convent against La Cassière, who was widely perceived to be the cause of these problems and humiliations.