The combination of the AR PROTAC AZD9750 and AKT inhibitor capivasertib delivers improved efficacy over monotherapy in prostate cancer

The PI3K-AKT pathway is frequently activated in prostate cancer through PTEN genetic alterations-primarily homozygous deletion in tumor cells-and is associated with poor clinical outcomes. Capivasertib, a potent, oral, selective inhibitor of AKT1/2/3, inhibits proliferation in prostate cancer cell lines with PTEN alterations. Preclinical evidence demonstrates reciprocal feedback between AR and PI3K-AKT signaling, providing a strong rationale for combined pathway blockade. Consistent with this, in the Phase III CAPItello-281 trial (NCT04493853), capivasertib plus abiraterone and ADT achieved a statistically significant improvement in radiographic progression-free survival versus abiraterone and ADT in patients with PTEN -deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). Abiraterone, an androgen receptor pathway inhibitor (ARPI), is a key standard-of-care treatment in mHSPC, yet resistance inevitably emerges via mechanisms such as AR amplification and ligand-binding domain mutations. AZD9750 is a novel AR-directed proteolysis targeting chimera (AR-PROTAC) that co-engages AR and the E3 ligase CRBN to promote AR ubiquitination and degradation, achieving deeper suppression of AR signaling and activity against both wild-type and mutant AR, with the potential to overcome resistance to current standards of care. Given the robust preclinical and clinical evidence supporting combinations of AKT inhibitors with AR pathway suppression, we evaluated whether AZD9750 could combine effectively with capivasertib in preclinical prostate cancer models. In vitro , combining AZD9750 and capivasertib in LNCaP (PTEN null) and VCaP (PTEN wt) cell lines enhanced antiproliferative activity and induced apoptosis, accompanied by inhibition of AKT pathway signaling (reduced pS6 and pPRAS40) and AR signaling (decreased PSA expression). In PTEN-null patient-derived xenograft prostate tumor models (both HSPC and CRPC), the combination consistently delivered significantly greater efficacy than either monotherapy, including 73% tumor growth inhibition (TGI) in TM00298 (vs AZD9750 52% TGI and capivasertib 14% TGI) and >100% TGI with 25% regression in MR041 (vs AZD9750 90% TGI and capivasertib 61% TGI), with similar benefits observed in other models. These findings indicate that in PTEN-null prostate cancer AZD9750 mediated AR degradation synergizes with AKT inhibition by capivasertib to enhance antitumor efficacy and support clinical evaluation of the AR-PROTAC-AKT inhibitor combination in PTEN-deficient prostate cancer.