Almost as soon as the wedding ceremony was over, the political situation changed with the invasion of Italy by King Charles VIII of France, who claimed Naples as his own.

Alfonso fled, leaving the throne to his short-lived son, and a long war between Spain, France and their Italian adherents ensued.

During this time the young couple lived mostly at Rome, where Sancha reputedly had affairs with both of her husband's elder brothers, Giovanni and Cesare, among others.

In 1504 he sent the condottiero Fabrizio Colonna to stabilise his lands, partly paid for with money he had appropriated from the papal treasury after the death of his father the year before.

After his death, the existence of a natural son, Geronimo, was also revealed, who was entrusted to his sister Lucrezia at the request of their mother Vannozza.