BrUOG360: A phase Ib/II study of copanlisib in combinationwith rucaparib in patients with metastatic castration-resistantprostate cancer (mCRPC)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) with homologous-recombination (HR) deficiency (HRD) is sensitive to PARP inhibitors (PARPi). PI3K inhibitors (PI3Ki) sensitize to PARPi by disrupting HR in pre-clinical models. We conducted a phase Ib/II study investigating copanlisib (Copa; pan-class I PI3Ki) and rucaparib (R). Patients and Methods: Eligible patients (pts) had mCRPC treated with >1 androgen receptor inhibitor and taxanes. Phase I followed a 3+3 dose-escalation design (R 400-600mg PO BID; Copa 45-60 mg IV Days 1,8,15). Primary goal of the phase I was to establish maximum-tolerate dose and the recommended phase II dose (RP2D). The primary endpoint of phase II was PSA50 response rate. Results: Thirteen pts enrolled had median age 64 (55-78), PSA 11.7 ng/ml (0.018-2101). Seven pts received taxanes, and 1 pt PARPi. Eight pts had HRD+ tumors (BRCA2 [4], BRCA1 [1], RAD51C [1], CDK12 [1], FANCA [1]) and 3 PTEN loss. There were two dose-limiting toxicities (DLTs) in dose level (DL) 1 (R 400mg BID, Copa 45mg D1, 8, 15): G3 rash and AST/ALT elevation. Treatment-related adverse events >G2 included leukopenia (54%), anemia (38%), rash (30%), fatigue (23%), and neutropenia (23%). Six pts were treated at DL -1 without DLTs, which was established as the RP2D (R 400 mg BID+Copa 45mg D1/15). Among pts with HRD+, 1 had cPR and 3 pts SD by RECIST including 1 pt treated with prior PARPi, 3pts had PSA50 responses (23%). Conclusions: Copa/R had a favorable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.