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

• DOI: 10.1200/jco.2023.41.16_suppl.5005
• Publication Date: 2023-06-04T15:49:12Z
• Authors: Shahneen Sandhu; Anthony M. Joshua; Louise Emmett; Megan Crumbaker; Mathias Bressel; Rhonda Huynh; Patricia Diana Banks; Roslyn Wallace; Anis Hamid; Andrisha Jade Ind...; Ben Tran; Arun Azad; Ramin Alipour; Grace Kong; Aravind Ravi Kumar; Javad Saghebi; Scott Williams; Timothy J. Akhurst; Rodney J. Hicks; Michael S Hofman
• Keywords: Olaparib; PARP inhibitor; Progression-free survival

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