FPI-2265 + olaparib

FPI-2265 + olaparib is an investigational combination therapy for metastatic castration-resistant prostate cancer (mCRPC). FPI-2265 (225Ac-PSMA-I&T) is a PSMA-directed targeted alpha therapy using actinium-225 radioisotope-labeled small molecules that selectively target the prostate-specific membrane antigen (PSMA) expressed on prostate cancer cells, delivering cytotoxic alpha particle radiation directly to tumor tissue[1][4][6]. Olaparib is a small molecule PARP inhibitor that prevents DNA repair in cancer cells, especially in those with homologous recombination repair deficiency such as BRCA mutations. The rationale for combining these agents is that alpha radiation from FPI-2265 induces double-strand DNA breaks, while olaparib impairs repair of such damage via PARP inhibition, resulting in synergistic anti-tumor effects[6]. The combination is being evaluated in Phase 2 clinical trials in mCRPC, including patients who previously received 177Lu-based radioligand therapy[1][4][6]. Preliminary results suggest enhanced anti-tumor activity and an acceptable safety profile, chiefly marked by mild to moderate xerostomia, thrombocytopenia, anemia, and fatigue[3][6][7]. FPI-2265 is being developed by Fusion Pharmaceuticals; olaparib was developed by AstraZeneca and Merck, though in this trial the combination was sponsored by Fusion Pharmaceuticals[3][6][8].