BrUOG360 Phase Ib/II Trial: Copanlisib Plus Rucaparib for mCRPC With HRD

Copanlisib combined with rucaparib demonstrates tolerability and early signals of activity in metastatic castration-resistant prostate cancer (mCRPC), according to results from the BrUOG360 phase Ib/II trial published in late 2025.
​Metastatic castration-resistant prostate cancer with homologous recombination deficiency (HRD) responds to PARP inhibitors like rucaparib, but many patients develop resistance through alternative DNA repair pathways. Preclinical models show PI3K inhibitors such as copanlisib can sensitize these tumors by disrupting homologous recombination, providing a strong rationale for this combination.

The trial enrolled heavily pretreated patients who had progressed on at least one androgen receptor inhibitor and taxane, with or without prior PARP exposure.  Safety data from 13 patients showed the regimen was manageable, with no new safety signals beyond known class effects.

Preliminary efficacy in the phase II portion focused on HRD-positive patients (defined by mutations in BRCA1/2, RAD51C, CDK12, FANCA, or PTEN loss). Among 13 evaluable patients (8 HRD+), the PSA50 response rate reached 23% (3 of 13), with one confirmed partial radiographic response and three cases of stable disease. Notably, one patient previously exposed to PARP inhibitors maintained stable disease, hinting at activity in resistant settings.

The combination’s potential lies in targeting concurrent HRD and PI3K pathway alterations, which occur in about 4% of mCRPC cases. Mechanistic studies suggest dual inhibition activates cGAS-STING signaling in tumor-associated macrophages, potentially enhancing T-cell infiltration, though this was not directly assessed here.

Source.​