Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH)

A Phase 3, Open-Label, Randomized Study Evaluating Metastatic Castrate Resistant Prostate Cancer Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH)

The purpose of this study is to evaluate the efficacy and safety of [Lu-177]-PNT2002 in patients with metastatic castration-resistant prostate cancer who have progressed following treatment with androgen receptor axis-targeted therapy (ARAT).

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Castration-Resistant Prostate Cancer
• Intervention / Treatment: Drug: [Lu-177]-PNT2002; Drug: Abiraterone; Drug: Enzalutamide

Detailed Description

The primary objective of the study is to determine the efficacy of [Lu-177]-PNT2002 ([Lu-177]-PSMA-I&T) versus abiraterone or enzalutamide in delaying radiographic progression in patients with mCRPC.

The study consists of 3 phases: Dosimetry, Randomized Treatment, and Long term Follow up.

The study will commence with a 25-patient safety and dosimetry lead-in (Part 1) and proceed to a randomization treatment phase in approximately 390 patients (Part 2). Patients in Part 2 will be randomized in a 2:1 ratio to receive either [Lu-177]-PNT2002 (Arm A), or enzalutamide or abiraterone (Arm B). Patients in Arm B who experience radiographic progression per central review and meet protocol defined eligibility, may crossover to receive [Lu-177]-PNT2002. After final overall survival (OS) analysis, all patients will continue to be followed through Continued Access, including long-term follow-up (LTFU) for at least 5 years from the first therapeutic dose, death, or loss to follow up (Part 3).

Only patients that meet PSMA PET avidity criteria per central review will be eligible for this study.

• Study Type: Interventional
• Enrollment (Actual): 455
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer - Vancouver
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Nova Scotia Health Authority
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center - Victoria Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute, Odette Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H2X 3E4
      • CHUM - University Hospital of Montreal
    • Québec, Quebec, Canada, G1R 2J6
      • CHU of Quebec - Laval University
• France
  • Clermont-Ferrand, France, 63011
    • Center Jean Perrin, Department of Medical Oncology
  • Lille, France, 59037
    • Claude Huriez hospital
  • Lyon, France, 69373
    • Léon Bérard Center
  • Marseille, France, 13385
    • La Timone Hospital, Nuclear Medicine Department
  • Montpellier, France, 34298
    • Montpellier Cancer Institute, Department of Nuclear Medicine
  • Paris, France, 75020
    • Tenon Hospital, Department of Medical Oncology
• Netherlands
  • Nieuwegein, Netherlands
    • St. Antonius Hospital
  • Nijmegen, Netherlands
    • Radboud University Medical Center (Radboudumc)
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus University Medical Center Rotterdam
• Sweden
  • Gothenburg, Sweden, 41345
    • Sahlgrenska University Hospital
  • Umeå, Sweden
    • Norrlands University Hospital, Department of Radiation Sciences, Oncology
• United Kingdom
  • London, United Kingdom
    • Charing Cross Hospital, Department of Medical Oncology
  • Sutton, United Kingdom
    • Royal Marsden NHS Foundation Trust - Institute of Cancer Research
• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Institute of Urology (AIU) - Tucson
  • California
    • Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles, Nuclear Medicine Clinic
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
    • Orange, California, United States, 92868
      • UC Irvine Chao Family Comprehensive Cancer Center
    • Palo Alto, California, United States, 94305
      • Stanford Cancer Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenebaum Cancer Center
    • Towson, Maryland, United States, 21204
      • Chesapeake Urology Associates (CUA) P.A.
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospitals
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
    • St Louis, Missouri, United States, 63106
      • VA St. Louis Health Care System
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Urology Cancer Center, PC
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Astera Cancer Care
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • New Mexico Oncology Hematology Consultants Ltd., New Mexico Cancer Center
  • New York
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital/Weill Cornell Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45212
      • Tri-State Urologic Services
    • Kettering, Ohio, United States, 45409
      • Greater Dayton Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Perelman Center for Advanced Medicine
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT southwestern Medical Center
    • Dallas, Texas, United States, 75216
      • Dallas VA Medical Center, Nuclear Medicine Service
    • Houston, Texas, United States, 77402
      • Excel Diagnostics & Nuclear Oncology Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male aged 18 years or older.
2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate.
3. Ineligible or averse to chemotherapeutic treatment options.

4. Patients must have progressive mCRPC at the time of consent based on at least 1 of the following criteria:

   1. Serum/plasma PSA progression defined as increase in PSA greater than 25% and >2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart.
   2. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or a new lesion.
   3. Progression of bone disease defined as the appearance of two or more new lesions by bone scan.
5. Progression on previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or apalutamide) in either the CSPC or CRPC setting.
6. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the sponsor's central reader.
7. Castrate circulating testosterone levels (<1.7 nmol/L or <50 ng/dL).

8. Adequate organ function, independent of transfusion:

   1. Bone marrow reserve:

      • i. White blood cell (WBC) count ≥2.5 × 10^9/L OR absolute neutrophil count (ANC) ≥1.5 × 10^9/L.
      • ii. Platelets ≥100 × 10^9/L.
      • iii. Hemoglobin ≥8 mmol/L.

   2. Liver function:

      • i. Total bilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with known Gilbert's syndrome, ≤3 × ULN is permitted.
      • ii. ALT or AST ≤3.0× ULN.

   3. Renal function:

      • i. Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula (for patients in France, serum/plasma creatinine ≤1.5 × ULN or CrCl ≥60 mL/min based on Cockcroft-Gault formula).
   4. Albumin ≥30 g/L.
9. Human immunodeficiency virus-infected patients who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial.
10. For patients who have partners who are pregnant or of childbearing potential: a condom is required along with a highly effective contraceptive method during the study and for 6 months after last study drug administration. Such methods deemed highly effective include a) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, b) progestogen-only hormonal contraception associated with inhibition of ovulation, c) intrauterine device (IUD), d) intrauterine hormone-releasing system (IUS), e) bilateral tubal occlusion, f) vasectomy, g) true sexual abstinence: when this is in line with the preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of abstinence].
11. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified by investigator, if randomized to Treatment Arm B.
12. ECOG performance status 0 to 1.
13. Willing and able to comply with all study requirements and treatments (including 177Lu PNT2002) as well as the timing and nature of required assessments.
14. Signed informed consent.

Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply:

1. If noted in pathology report, prostate cancer with known significant (>10% present in cells) sarcomatoid or spindle cell or neuroendocrine components. Any small cell component in the cancer should result in exclusion.
2. Prior treatment for prostate cancer ≤28 days prior to randomization, with the exclusion of first-line local external beam, ARAT, luteinizing hormone-releasing hormone (LHRH) therapy, or non-radioactive bone-targeted agents.
3. Any prior cytotoxic chemotherapy for CRPC (e.g., cabazitaxel or docetaxel); chemotherapy for hormone-sensitive prostate cancer (HSPC) is allowed if the last dose was administered >1 year prior to consent.
4. Prior treatment with systemic radionuclides (e.g. radium-223, rhenium-186, strontium 89).
5. Prior immuno-therapy, except for sipuleucel-T.
6. Prior PSMA-targeted radioligand therapy, e.g., Lu-177-PSMA-617, I 131-1095.
7. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer.
8. Patients who progressed on 2 or more lines of ARATs.
9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) not on stable doses for at least 4 weeks prior to randomization.
10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to randomization.
11. Major surgery ≤30 days prior to randomization.
12. Estimated life expectancy <6 months as assessed by the principal investigator.
13. Presence of liver metastases >1 cm on abdominal imaging.
14. A superscan on bone scan defined as a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint genitourinary tract activity.
15. Dose escalation or initiation of opioids for cancer-related pain ≤30 days prior to consent up to and including randomization.
16. Known presence of central nervous system metastases.

17. Contraindications to the use of planned ARAT therapy, [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002 therapy, including but not limited to the following:

    • Hypersensitivity to [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002 excipients (Diethylenetriaminepentaacetic acid (DTPA), Sodium ascorbate, Lascorbic acid, Sodium gentisate, HCl, Sodium hydroxide).
    • Recent myocardial infarction or arterial thrombotic events (in the past 6 months) or unstable angina (in the past 3 months), bradycardia or left ventricular ejection fraction measurement of < 50%.
    • History of seizures in patients planned to receive enzalutamide.
18. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer.
19. Concurrent illness that may jeopardize the patient's ability to undergo study procedures.
20. Serious psychological, familial, sociological, or geographical condition that might hamper compliance with the study protocol and follow-up schedule. Patients that travel need to be capable of repeated visits even if they are on the control arm.
21. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
22. Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure (see 12.1 Appendix 1), unstable ischemia, uncontrolled symptomatic arrhythmia, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lead-in Dosimetry Phase: [Lu-177]-PNT2002; Participants received 6.8 gigabecquerels (GBq) (±10%) of [Lu-177]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.	Drug: [Lu-177]-PNT2002; Participants randomized to Arm A will receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 every 8 weeks for 4 cycles; Other Names: [Lu-177]-PSMA-I&T; LY4187525
Experimental: Randomization Phase: [Lu-177]-PNT2002 (Arm A); Participants received 6.8 GBq (±10%) of [Lu-177]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.	Drug: [Lu-177]-PNT2002; Participants randomized to Arm A will receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 every 8 weeks for 4 cycles; Other Names: [Lu-177]-PSMA-I&T; LY4187525
Active Comparator: Randomization Phase: Abiraterone or Enzalutamide (Arm B); Participants received either of below treatments until radiographic progression.; Enzalutamide 160 milligram (mg) orally once daily (or); Abiraterone 1000 mg orally once daily coadministered with prednisone 5 mg orally twice daily or dexamethasone 0.5 mg orally once daily. Participants who experienced radiographic progression per Blinded Independent Central Review (BICR) (or after final overall survival (OS), per local investigator-assessment), had not started an intervening treatment, and had no uncontrolled adverse events (AEs) were eligible to consent to cross over to receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 intravenous infusion every 8 weeks for 4 cycles.	Drug: [Lu-177]-PNT2002; Participants randomized to Arm A will receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 every 8 weeks for 4 cycles; Other Names: [Lu-177]-PSMA-I&T; LY4187525; Drug: Abiraterone; Abiraterone (1000 mg orally once daily with: 5 mg twice daily prednisone or 0.5 mg once daily dexamethasone); Drug: Enzalutamide; Enzalutamide (160 mg orally once daily)
Experimental: Pharmacokinetic (PK) Extension Phase: [Lu-177]-PNT2002; Participants received 6.8 GBq (±10%) of [Lu-177]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.	Drug: [Lu-177]-PNT2002; Participants randomized to Arm A will receive 6.8 GBq (±10%) of [Lu-177]-PNT2002 every 8 weeks for 4 cycles; Other Names: [Lu-177]-PSMA-I&T; LY4187525

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Randomization Phase: Radiographic Progression-Free Survival (rPFS)	rPFS, as assessed by blinded independent central review (BICR), is the time from the randomization date to progression on soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or confirmed progression on bone lesions by Prostate Cancer Working Group 3 (PCWG3) criteria, or death from any cause.; The date of disease progression is the date of the scan for the first objectively documented progressive disease (PD) per RECIST v1.1 or PCWG3. PD is defined as a ≥20% increase in the sum of the diameters of target lesions (≥5 mm absolute), with reference being the smallest sum in the study, or unequivocal progression of non-target lesions, or appearance of new lesions.; Participants who do not progress, including those who started new anticancer therapy, withdrew from the study, or were lost to follow-up without disease progression, were censored at the last valid assessment for RECIST v1.1 or PCWG3.	From the randomization date to the first documented progressive disease or death from any cause (up to 23 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Time from the date of randomization until death due to any cause.	5 years
Randomization Phase: Percentage of Participants With Objective Response Rate (ORR)	ORR, as assessed by BICR, is the best confirmed overall tumor response of complete response (CR) or partial response (PR) as per RECIST v1.1 ( in the absence of confirmed progression on bone scan assessed by PCWG3).; CR is a disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm).; PR is at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), without progression of non-target lesions or appearance of new lesions.	Randomization until measured progressive disease (up to 23 months)
Randomization Phase: Duration of Response	Duration of Response, as assessed by BICR, is the time from the date of first documented confirmed CR or PR as per RECIST v1.1 (in the absence of confirmed progression on bone scan assessed by PCWG3) to the date of first documented radiographic progression or death in the absence of progression. Participants who have attained CR or PR as the best overall response, did not have progressive disease, and did not die will be censored.	From the date of first CR or PR to disease progression or death (up to 16.3 months)
Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate	The PSA response rate, as per the PCWG3 criteria, is the percentage of participants achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second PSA assessment conducted at least 3 weeks later.	From the randomization up to 23 months
Randomization Phase: Biochemical Progression-Free Survival (bPFS)	bPFS is the time from the date of randomization to the date of the first PSA increase from baseline ≥25% and ≥2 nanograms per milliliter (ng/mL) above nadir confirmed by a second PSA measurement defining progression ≥3 weeks later, as per PCWG3, or death from any cause in the absence of progression. Participants who do not progress or die including those who withdraw from the study or are lost to follow-up will be censored at the time of last valid PSA measurement.	From the randomization up to 23 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability (AEs)	Frequency and severity of AEs, graded and categorized using CTCAE v. 5.0.	5 years

Collaborators and Investigators

• Sponsor: POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
• Investigators: Study Director: Jessica Jensen, Eli Lilly and Company

Publications and helpful links

General Publications

• Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. 2016 Jul;57(7):1006-13. doi: 10.2967/jnumed.115.168443. Epub 2016 Jan 21.
• Hansen AR, Probst S, Beauregard JM, Viglianti BL, Michalski JM, Tagawa ST, Sartor O, Tutrone RF, Oz OK, Courtney KD, Delpassand ES, Nordquist LT, Osman MM, Chi KN, Sparks R, George N, Hawley SM, Wu W, Jensen JD, Fleshner NE. Initial clinical experience with [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer: dosimetry, safety, and efficacy from the lead-in cohort of the SPLASH trial. Front Oncol. 2025 Jan 7;14:1483953. doi: 10.3389/fonc.2024.1483953. eCollection 2024.
• American College of Nuclear Medicine (ACNM) 2022 ACNM Annual Meeting AbstractsJanuary 27-29, 2022 Virtual Meeting. Clin Nucl Med. 2023 Feb 3:e246-e277. doi: 10.1097/RLU.0000000000004535. Online ahead of print. No abstract available.

Helpful Links

• 1400P - Efficacy and safety of 177Lu-PNT2002 prostate-specific membrane antigen (PSMA) therapy in metastatic castration resistant prostate cancer (mCRPC): Initial results from SPLASH
• ESMO 2024: Efficacy of 177Lu-PNT2002 in PSMA-Positive mCRPC Following Progression on an Androgen-Receptor Pathway Inhibitor (SPLASH)

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Actual): November 1, 2023
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: November 23, 2020
• First Submitted That Met QC Criteria: November 23, 2020
• First Posted (Actual): December 1, 2020

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Prostate cancer; mCRPC; PSMA; 177Lu-PSMA; radioligand therapy; PSMA-I&T; SPLASH
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; abiraterone; enzalutamide
• Other Study ID Numbers: 27232; PBP-301 (Other Identifier: POINT Biopharma Global Inc); J5T-OX-JXCA (Other Identifier: Eli Lilly and Company); 2021-002641-15 (EudraCT Number); 2024-515604-39-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No