I-131-1095 Radioligand Plus Enzalutamide vs Enzalutamide for mCRPC That Progressed During Abiraterone (ARROW). (ARROW)

A Multicenter, Randomized, Controlled Phase 2 Study: Efficacy and Safety of I-131-1095 Radiotherapy in Combination With Enzalutamide in mCRPC Patients Who Are 18F-DCFPyL PSMA-avid, Chemotherapy-naïve, and Progressed on Abiraterone (ARROW )

This clinical trial was done to show whether a radioactive drug (I-131-1095) that binds to prostate-specific membrane antigen (PSMA) is useful in treating metastatic prostate cancer that is positive for PSMA. The trial enrolled men whose PSMA-positive metastatic prostate cancer had progressed while they were taking abiraterone. During the trial, all of the men took enzalutamide (standard-of-care therapy) once a day. However, some of the men also had up to 4 doses (8 weeks apart) of I-131-1095 (in addition to taking enzalutamide once a day). At specified times during the trial, all of the men had blood tests (to measure levels of prostate-specific antigen [PSA]) and imaging studies (to assess tumor status). The two groups of men were then compared in several ways. The main comparison was the percentage of men in each group with at least a 50% decrease in PSA levels. Other comparisons involved the response of the tumors (as seen on imaging) and overall survival. To assess safety, the number of adverse events in both groups were also compared.

Study Overview

• Status: Completed
• Conditions: Castration-resistant Prostate Cancer; Metastatic Prostate Cancer; Cancer of the Prostate; Prostatic Neoplasm; Progressive mCRPC
• Intervention / Treatment: Drug: Enzalutamide; Drug: I-131-1095

Detailed Description

This phase 2 clinical trial (conducted in the United States and Canada) enrolled chemotherapy-naïve men whose PSMA-positive (as shown by piflufolastat F18 imaging) metastatic prostate cancer had progressed during treatment with abiraterone. The participants were stratified by risk factors at Screening and then randomized 2:1 either to receive PSMA radioligand therapy (up to four 8-week cycles of I-131-1095) plus standard treatment with enzalutamide or to receive standard treatment with enzalutamide as monotherapy. The prostate-specific antigen (PSA) levels and radiographic response or progression (RECIST v1.1 criteria for soft tissue and PCWG3 criteria for bone) were then monitored for up to 53 weeks of randomized treatment. The primary outcome measure was PSA response rate (percentage of participants with a confirmed ≥50% decrease in serum PSA). Other outcome measures included percentage of participants with partial or complete response (radiographic), duration of response, time to progression (PSA or radiographic), time to next treatment for prostate cancer, and overall survival.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital
    • Toronto, Ontario, Canada
      • London Health Sciences Centre
    • Toronto, Ontario, Canada
      • University Health Network - Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada
      • Jewish General Hospital
    • Montreal, Quebec, Canada
      • Centre Hospitalier Del' Universite de Montreal
    • Québec, Quebec, Canada
      • Centre Hospitalier Universitaire de Quebec
    • Sherbrooke, Quebec, Canada
      • Centre Hospitalier Universitaire de Sherbrooke
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System
    • Los Angeles, California, United States, 90095-7370
      • UCLA
    • Newport Beach, California, United States, 92663
      • Hoag Family Cancer Institute
    • Palo Alto, California, United States, 94303
      • VA Palo Alto Healthcare System
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical School
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 09206
      • Lifespan Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male ≥ 18 years of age
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis
3. Castration-resistant prostate cancer, with serum testosterone ≤ 50 ng/dL at Screening
4. Radiographic evidence of metastatic disease prior to Randomization or up to 21 days prior to Screening

5. Disease progression on prior abiraterone therapy as defined by meeting at least one of the following criteria per the investigator:

   1. PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart
   2. Soft tissue disease progression defined by RECIST 1.1
   3. Bone disease progression defined by two or more new lesions on bone scan
6. Planned to receive treatment with enzalutamide

7. Subjects who are ineligible or choose not to receive taxane-based chemotherapy based on personal preference or physician opinion. Examples of conditions that could make a patient ineligible or refuse to receive taxane-based chemotherapy, but would allow them to still be eligible to receive I-131-1095 include the following:

   1. Poor performance status
   2. Prior intolerance to cytotoxic agents
   3. History of another malignancy suspected for recurrence or metastases
   4. Other serious medical conditions such as symptomatic peripheral neuropathy CTCAE Grade 2 or higher; or clinically significant cardiovascular disease per the Investigator or treating physician
8. Subjects receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Randomization
9. ECOG performance status 0-2
10. If sexually active, agree to use a medically acceptable method of birth control or sexual abstinence from the time of dosing through 28 days after the last dose of I-131-1095. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
11. Estimated life expectancy of at least 6 months as determined by the Investigator.
12. Able and willing to provide signed informed consent and comply with protocol requirements

Exclusion Criteria:

1. Received any anti-tumor therapy within 4 weeks of Randomization, with the exception of abiraterone, GnRH therapy and non-radioactive bone-targeted agents
2. Received prior chemotherapy for castration-resistant prostate cancer
3. Superscan as evidenced on baseline bone scan
4. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Randomization
5. Prior hemi-body irradiation
6. Prior PSMA-targeted radioligand therapy
7. Major surgery within 4 weeks of Randomization

8. Impaired organ function as evidenced by the following laboratory values at Screening:

   1. Absolute neutrophil count < 1500 μL
   2. Platelet count < 100,000/μL
   3. Hemoglobin < 9.5 g/dL
   4. Albumin < 3.0 g/dL (30 g/L)
   5. Total bilirubin > 2 x ULN unless in instances of known or suspected Gilbert's disease
   6. AST or ALT > 2.5 x ULN
   7. Calculated creatinine clearance (CrCL) < 30 mL/min (Cockroft-Gault equation), or currently on renal dialysis.
9. QT interval corrected for heart rate (QTc) > 470 msec
10. Previous use of enzalutamide for more than 7 days prior to consent
11. Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study
12. History or risk of seizure (i.e., clinically significant neurological disorder) or any other condition that contraindicates treatment with enzalutamide
13. Gastrointestinal disorder affecting absorption of oral medications
14. Known or suspected brain metastasis or active leptomeningeal disease
15. Active malignancy other than prostate cancer, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or non-muscle invasive bladder/urothelial cancer
16. Subjects with any medical condition or other circumstances that, in the opinion of the investigator, compromise obtaining reliable data, achieving study objectives, or completing the study.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Enzalutamide; Participants received the label dosage of enzalutamide once daily for up to 53 weeks.	Drug: Enzalutamide; Participants received the label dosage of enzalutamide once daily for up to 53 weeks.; Other Names: Xtandi
Experimental: I-131-1095 in combination with enzalutamide; Participants received up to 4 (8-week) cycles of I-131-1095: 100 mCi for the first dose. Subsequent dose(s) were reduced to 75 mCi for participants experiencing any of the dose-limiting toxicities. The third and fourth therapeutic doses could be reduced to 75 mCi on the basis of dosimetry assessment after administration of 10 mCi of I-131-1095 prior to the third dosing cycle. Participants also received the label dosage of enzalutamide once daily for up to 53 weeks.	Drug: Enzalutamide; Participants received the label dosage of enzalutamide once daily for up to 53 weeks.; Other Names: Xtandi; Drug: I-131-1095; Participants received up to 4 (8-week) cycles of I-131-1095: 100 mCi for the first dose. Subsequent dose(s) were reduced to 75 mCi for participants experiencing any dose-limiting toxicities. The third and fourth therapeutic doses could be reduced to 75 mCi on the basis of dosimetry assessment after administration of 10 mCi of I-131-1095 prior to the third dosing cycle. Participants also received the label dosage of enzalutamide once daily for up to 53 weeks.; Other Names: 131 I-PSMA-1095; 131I-LNTH-1095

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA Response Rate	The percentage of participants with a PSA response according to PCWG3 criteria. PCWG3 defines PSA response as the first occurrence of a 50 percent or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later.	Up to 53 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The proportion of participants who have a partial response (PR) or complete response (CR) based on RECIST 1.1 for soft tissue or PCWG3 for bone (PCWG3-modified RECIST 1.1).	Up to 53 weeks
Overall Survival (OS)	Overall Survival is defined as time from randomization to death from any cause.	Up to 5 years
PSA Progression	Time from randomization to the date of the first PSA increase from baseline ≥ 25 percent and ≥ 2 ng/ml above nadir confirmed by a second PSA assessment defining progression ≥ 3 weeks later per PCWG3.	Up to 53 weeks
Radiographic Progression Free Survival (rPFS)	Time from randomization to the first occurrence of radiographic progression based on RECIST 1.1 for soft tissue (≥20% increase in the sum of the longest diameter of the target lesions [relative to the smallest value recorded since the treatment started] or the appearance of ≥1 new lesion) or PCWG3-modified RECIST 1.1 for bone, respectively, or unequivocal clinical progression, or death on study from any cause.	Up to 5 years.
Duration of Response	Time from the first date of complete response (CR) or partial response (PR) to the first occurrence of radiographic progression based on PCWG3-modified RECIST 1.1, or unequivocal clinical progression. Complete response was defined as disappearance of all target lesions. Partial response was defined as ≥30% decrease from baseline in the sum of the longest diameter of target lesions.	Up to 5 years.
Time to Initiation of Next Treatment for Prostate Cancer	Time from randomization to initiation of any new treatment for prostate cancer.	Up to 5 years

Collaborators and Investigators

• Sponsor: Progenics Pharmaceuticals, Inc.
• Investigators: Study Director: Jean-Claude Provost, MD, Progenics Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Afshar-Oromieh A, Haberkorn U, Zechmann C, Armor T, Mier W, Spohn F, Debus N, Holland-Letz T, Babich J, Kratochwil C. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with 131I-MIP-1095. Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):950-959. doi: 10.1007/s00259-017-3665-9. Epub 2017 Mar 9.
• Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, Joyal J, Kopka K, Debus J, Babich JW, Haberkorn U. Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014 Jul;41(7):1280-92. doi: 10.1007/s00259-014-2713-y. Epub 2014 Feb 28.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2019
• Primary Completion (Actual): September 21, 2023
• Study Completion (Actual): September 24, 2024

Study Registration Dates

• First Submitted: May 3, 2019
• First Submitted That Met QC Criteria: May 6, 2019
• First Posted (Actual): May 7, 2019

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: bone metastases; biomarker; docetaxel; radioligand therapy; dosimetry; SPECT/CT; PSMA PET; 18F-DCFPyL; PSMA-avidity; adjunct radiation therapy
• 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; enzalutamide
• Other Study ID Numbers: 1095-2301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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