Abstract: The present disclosure relates to a combination therapy with an anti-Trophoblast cell surface antigen 2 (Trop-2) antibody drug conjugate (anti-Trop-2 ADC) and a poly (ADP-ribose) polymerase inhibitor (PARPi) using a staggered dosing schedule. The ADC preferably incorporates an inhibitor of type I topoisomerase, such as SN-38 or DXd. The ADC is preferably administered prior to the PARPi in each cycle of the staggered dosing schedule. The combination therapy can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies. The schedules and dosages show efficacy against tumors, while exhibiting only manageable toxicity to normal tissues. Use of staggered dosing of an anti-Trop-2 ADC and a PARPi can reduce toxicity, for example relative to alternative dosing schedules involving daily administrations of the PARPi on each day of a cycle.