Aaron Hansen ^1* Stephan Probst ² Jean-Mathieu Beauregard ³ Benjamin L Viglianti ⁴ Jeff M Michalski ⁵ Scott T Tagawa ⁶ Oliver Sartor ⁷ Ronald F Tutrone ⁸ Orhan K Oz ⁹ Kevin D Courtney ¹⁰ Ebrahim S Delpassand ¹¹ Luke T Nordquist ¹² Medhat M Osman ¹³ Kim N Chi ¹⁴ Richard Sparks ¹⁵ Sara M Hawley ¹⁶ Wenting Wu ¹⁶ Jessica D Jensen ¹⁶ Neil E Fleshner ¹⁶

• ¹ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
• ² Jewish General Hospital, Montreal, Quebec, Canada
• ³ Department of Medical Imaging, CHU de Québec – Université Laval, Quebec City, QC, Canada
• ⁴ University of Michigan, Ann Arbor, MI, United States
• ⁵ Washington University School of Medicine, Saint Louis, MO, United States
• ⁶ Weill Cornell Medical Center, NewYork-Presbyterian, New York City, New York, United States
• ⁷ Mayo Clinic, Rochester, Minnesota, United States
• ⁸ Chesapeake Urology Associates (CUA) P.A., Towson, MD, United States
• ⁹ Department of Radiology, UT Southwestern, Dallas, TX, United States
• ¹⁰ Department of Internal Medicine, UT Southwestern, Dallas, TX, United States
• ¹¹ Excel Diagnostics & Nuclear Oncology Center, Houston, TX, United States
• ¹² Urology Cancer Center, PC, Omaha, NE, United States
• ¹³ Saint Louis University Hospital and St. Louis VA Medical Center, St. Louis, MO, United States
• ¹⁴ Department of Medicine, University of British Columbia, Vancouver, BC, Canada
• ¹⁵ CDE Dosimetry Services, Knoxville, TN, United States
• ¹⁶ POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company, Indianapolis, IN, United States

Introduction: SPLASH (NCT04647526) is a multicenter phase III trial evaluating the efficacy and safety of [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). This study leveraged a lead-in phase to assess tissue dosimetry and evaluate preliminary safety and efficacy, prior to expansion into a randomized phase. Here we report those results. Methods: Enrolled participants had mCRPC that progressed on one prior androgen receptor pathway inhibitor (ARPI), were prostate-specific membrane antigen (PSMA) PET-positive as determined by a central reader, were chemotherapy-naïve for mCRPC, and had adequate bone marrow and end-organ reserve. Participants received up to 4 cycles of [177Lu]Lu-PNT2002 at 6.8 GBq (±10%) intravenously per cycle every 8 weeks. Dosimetry (planar + SPECT/CT [n=7]; planar only [n=20]), safety, prostate-specific antigen (PSA) response, objective response rate (ORR), and radiographic progression-free survival (rPFS) per blinded independent central review were assessed. Results: Of 34 individuals screened, 32 underwent PSMA-PET/CT; 27 met all eligibility criteria. Median (range) age was 72 (57-86) years; all participants were enrolled in North America; 40.7% initiated prior ARPI treatment without distant metastases (M0) and 25.9% while hormone sensitive. Nineteen of 27 (70.4%) participants completed all 4 planned cycles. Organs receiving the largest mean (median, range) specific absorbed doses were lacrimal glands at 1.2 (0.9, 0.4-6.7) Gy/GBq (planar only [n=27]), followed by kidneys at 0.73 (0.63, 0.22-1.8) Gy/GBq (planar + SPECT/CT [n=7]; planar only [n=20]). Mean (median, range) tumor specific absorbed dose was 4.3 (2.1, 0.3-33.4) Gy/GBq (approximately 29 Gy/cycle) based on planar + SPECT/CT of 21 lesions in seven participants. [177Lu]Lu-PNT2002 was associated with no treatment-related deaths, few treatment-related grade ≥3 treatment-emergent adverse events (TEAEs), and no discontinuations for unacceptable toxicity. Treatment-related TEAEs occurring in ≥10% of participants included dry mouth (22.2%; all grade 1), fatigue (18.5%; grades 1-2), nausea (18.5%; grades 1-2), and anemia (14.8%; grades 1-3). Median (95% CI) rPFS was 11.5 (9.2-19.1) months, a PSA decline of ≥50% occurred in 42.3% (11/26) of participants, and confirmed ORR for evaluable disease was 50% (n=105/10).[ 177 Lu]Lu-PNT2002, administered at 6.8 GBq/cycle for 4 cycles, demonstrated a favorable dosimetry and safety profile, as well as promising preliminary efficacy.