Phase 1/2 PARTHENON Trial: AZD4956 Targets HRD in Advanced Prostate Cancer

The PARTHENON trial tests AZD4956, an experimental oral drug that blocks SMARCA2, a protein helping cancer cells rearrange their DNA to keep growing. In tumors already “weak” at fixing DNA damage due to homologous recombination deficiency (HRD), shutting down SMARCA2 creates a double hit: cells can’t remodel chromatin or repair errors, leading to collapse. This synthetic lethality approach targets late-stage cancers like prostate that carry HRD signatures.
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For prostate cancer patients, especially those with metastatic castration-resistant disease (mCRPC), the fit is strong. HRD hits 20-30% of mCRPC cases through mutations in BRCA1/2 (~10-15%), ATM (~10%), or other genes, making tumors vulnerable after standard hormone therapies, chemo, or even PARP inhibitors like olaparib fail.
AZD4956 will be initially tested tested solo and paired with saruparib (a targeted PARP1 inhibitor) and then other agents to overcome resistance.
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Clinical trial.