Phase 1b/2 AZD9574 PARP1 inhibitor + AZD2265 (FPI-2265) PSMA-targeted actinium-225 alpha radioconjugate in mCRPC.

AstraZeneca’s open-label, multi-center platform study in metastatic prostate cancer includes Sub-study 1 for metastatic castration-resistant prostate cancer (mCRPC), testing AZD9574 (a PARP1-selective small-molecule PARP inhibitor) combined with AZD2265/FPI-2265 (a PSMA-targeted small-molecule radioconjugate labeled with actinium-225, an alpha emitter that causes lethal DNA damage at short range). Part A dose-escalates the combination; Part B evaluates a selected combination dose and compares against FPI-2265 monotherapy and standard docetaxel chemotherapy, with endpoints including radiographic progression-free survival and PSA response metrics. Eligible participants are progressive, unresectable mCRPC after prior androgen receptor pathway inhibitor therapy, with a PSMA-positive cohort in Sub-study 1. The commercial/scientific angle is pairing high-LET targeted alpha PSMA radiotherapy with DDR blockade to potentially deepen responses beyond today’s mCRPC sequencing of continued androgen deprivation plus ARPIs, taxane chemo (docetaxel/cabazitaxel), PARP inhibitors in HRR-altered disease, and PSMA radioligand therapy where available.