This Spanish invasion Rome resented.

She grew restive under it.
Roderigo's elder brother, Don Pedro Luis de Lanzol y Borja, was made Gonfalonier of the Church, Castellan of all pontifical fortresses and Governor of the Patrimony of St.Peter, with the title of Duke of Spoleto and, later, Prefect of Rome, to the displacement of an Orsini from that office.

Calixtus invested this nephew with all temporal power that it was in the Church's privilege to bestow, to the end that he might use it as a basis to overset the petty tyrannies of Romagna, and to establish a feudal claim on the Kingdom of Naples.
Here already we see more than a hint of that Borgia ambition which was to become a byword, and the first attempt of this family to found a dynasty for itself and a State that should endure beyond the transient tenure of the Pontificate, an aim that was later to be carried into actual--if ephemeral--fulfilment by Cesare Borgia.
The Italians watched this growth of Spanish power with jealous, angry eyes.

The mighty House of Orsini, angered by the supplanting of one of its members in the Prefecture of Rome, kept its resentment warm, and waited.

When in August of 1458 Calixtus III lay dying, the Orsini seized the chance: they incited the city to ready insurgence, and with fire and sword they drove the Spaniards out.
Don Pedro Luis made haste to depart, contrived to avoid the Orsini, who had made him their special quarry, and getting a boat slipped down the Tiber to Civita Vecchia, where he died suddenly some six weeks later, thereby considerably increasing the wealth of Roderigo, his brother and his heir.
Roderigo's cousin, Don Luis Juan, Cardinal-Presbyter of Santi Quattro Coronati, another member of the family who owed his advancement to his uncle Calixtus, thought it also expedient to withdraw from that zone of danger to men of his nationality and name.
Roderigo de Lanzol y Borja alone remained--leastways, the only prominent member of his house--boldly to face the enmity of the majority of the Sacred College, which had looked with grim disfavour upon his uncle's nepotism.