LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC).

5005 Background: 177 Lu-PSMA-617, a PSMA-directed, radionuclide therapy improves progression free survival (PFS) and overall survival (OS) in patients (pts) with mCRPC. Although many pts benefit from treatment, approximately a third have primary resistance, median PFS is 5.1 months and all pts inevitably relapse. Poly (ADP-ribose) polymerase (PARP) is implicated in repairing radiation-induced DNA single-strand breaks (SSBs). The potent PARP inhibitor (PARPi) olaparib results in the conversion of DNA SSBs to lethal double-strand breaks. Multiple preclinical studies have shown enhanced anti-tumor activity from combined PARPi and radiotherapy. LuPARP aims to evaluate the safety and efficacy of the combination of 177 Lu-PSMA-617 and olaparib. Methods: 48 pts with mCRPC and high PSMA expression (SUVmax 15 at a site of disease, and SUVmax ≥ 10 at other measurable sites) without discordant FDG positive/PSMA negative disease will be enrolled in two stages: dose-escalation (standard 3+3 design) and dose-expansion at the recommended phase 2 dose (RP2D). 177 Lu-PSMA-617 is administered at 7.4 GBq IV on day 1, every 6 weeks for up to 6 cycles in conjunction with 9 prespecified dose schedules of olaparib. The dose-limiting toxicity (DLT) period is 6 weeks. The primary objectives are establishing the DLTs and RP2D. Secondary objectives are toxicity, radiological PFS (rPFS), PSA response rate (PSA50-RR), PSA-PFS, objective response rate (ORR) and OS. Responses are assessed by 3-weekly PSA and conventional and PSMA PET/CT imaging every 12 weeks. Results: 29 pts (median age 70 years: range: 52-84; prior docetaxel: 97%; prior androgen receptor pathway inhibitor: 100%) received 177 Lu-PSMA-617 on day 1 with escalating doses of olaparib (cohorts 1-6: 50mg - 300 mg BD days 2-15) or alternate olaparib schedules (cohort 7: 200 BD days - 4 to 14; cohort 8: 300 BD days - 4 to 14; cohort 9: 300 mg BD days -4 to 18) for up to 6 cycles. No DLTs were reported. Common treatment related adverse events (TRAE) (≥10%) were Grade (G) 1-2 and included xerostomia (83%), nausea (62%), fatigue (34%), constipation (31%), anorexia (17%), vomiting (14%) and diarrhea (10%). Hematologic TRAE included anemia (G1: 14%; G2: 7%; G3: 7%), thrombocytopenia (G1: 14%; G2: 7%; G3: 3%) and neutropenia (G1: 3%; G3: 7%) that were transient and without clinical sequelae. Across cohorts 1-9, the PSA50-RR was 62% (18/29) and PSA90-RR was 48% (14/29). Five of the 7 pts (71%) with RECIST measurable disease had a partial response. Conclusions: The combination of 177 Lu-PSMA-617 and olaparib is well tolerated and has promising activity. Three further patients are being enrolled to cohort 9 to confirm the RP2D ahead of dose-expansion. Clinical trial information: NCT03874884 . [Table: see text]