177Lu-PSMA-617 vs. Androgen Receptor-Directed Therapy in the Treatment of Progressive Metastatic Castrate Resistant Prostate Cancer

NCT04689828 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 2 other identifiers: CAAA617B123022023-507772-50-00
• Study Type: interventional
• Target: 469
• Locations: 14 countries
• Sites: 72

Brief Summary

The purpose of this study is to determine whether 177Lu-PSMA-617 improves the Radiographic progression-free survival (rPFS) or Overall Survival (OS) compared to a change in Androgen receptor-directed therapy (ARDT) in metastatic castrate resistant prostate cancer (mCRPC) participants that were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen in the CRPC or mHSPC settings. 469 participants were randomized (235 in the 177Lu-PSMA-617 group and 234 in the ARDT group.

Conditions

Prostatic Neoplasms

Keywords

177Lu-PSMA-617; Androgen receptor-directed therapy; ARDT; Metastatic castrate resistant prostate cancer; mCRPC; Radiographic progression free survival; rPFS; Castrate resistant prostate cancer; CRPC; Prostate-specific membrane antigen; PSMA

Outcome Measures

Primary Outcomes (1)

• Radiographic Progression Free Survival (rPFS)

  rPFS is defined as the time to radiographic progression by Prostate cancer working Group 3 (PCWG3)-modified RECIST v1.1 as assessed by Blinded independent central (BICR) review or death.

  median FU (randomization to event or censoring) 3.65 months (range 0-12.3)

Secondary Outcomes (12)

• Overall Survival (OS) (Key Secondary Endpoint)

  approx. 26.9 months from randomization to cut-off

• Radiographic Progression Free Survival 2 (rPFS2) by Blinded Independent Central Review (BICR)

  From date of crossover until second radiographic progression or death, whichever comes first, assessed up to approx. 32 months

• Progression Free Survival (PFS) by Investigator's Assessment

  From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed upFrom date of randomization until date of death from any cause, assessed up to approx. 32 months

• Second Progression Free Survival (PFS2) by Investigator's Assessment

  From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to approx. 32 months

• PSA50 Response

  Weeks 12, 24, 48 and anytime during randomized phase

Study Arms (2)

177Lu-PSMA-617

EXPERIMENTAL

Participants received 7.4 GBq (200 mCi) +/- 10% 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT could be used.

Drug: 177Lu-PSMA-617; Drug: 68Ga-PSMA-11

Androgen receptor-directed therapy (ARDT)

ACTIVE COMPARATOR

For participants randomized to the ARDT arm, abiraterone or enzalutamide was administered per the physician's orders. Best supportive care, including Androgen deprivation therapy (ADT) could be used.

Drug: 68Ga-PSMA-11; Drug: ARDT

Interventions

177Lu-PSMA-617 DRUG

administered intravenously once every 6 weeks (1 cycle) for 6 cycles

177Lu-PSMA-617

68Ga-PSMA-11 DRUG

single intravenous dose of approximately 150 MBq. Administered dose must not be lower than 111 MBq or higher than 185 MBq (3 - 5 mCi).

177Lu-PSMA-617; Androgen receptor-directed therapy (ARDT)

ARDT DRUG

administered orally on a continuous basis, as per package insert and guidelines

Also known as: Comparator

Androgen receptor-directed therapy (ARDT)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Gender Eligibility Details: Prostate cancer study.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent must be obtained prior to participation in the study.
• Participants must be adults \>= 18 years of age.
• Participants must have an ECOG performance status of 0 to 1.
• Participants must have histological pathological, and/or cytological confirmation of adenocarcinoma of the prostate.
• Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader.
• Participants must have a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).
• Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide).
• First generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior ARDT therapy.
• Second generation ARDT must be the most recent therapy received.
• Participants must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:
• Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression.
• Soft-tissue progression defined \[PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)\].
• Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016)).
• Participants must have \>= 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained prior to randomization.
• Participants must have recovered to =\< Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia.

You may not qualify if:

• Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation.
• Previous PSMA-targeted radioligand therapy.
• Prior treatment with cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy \[including monoclonal antibodies\]. \[Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed\].
• Any investigational agents within 28 days prior to day of randomization.
• Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes.
• Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy.
• Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
• Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
• History or current diagnosis of the following ECG abnormalities indicating significant risk of safety for study participants:
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
• History of familial long QT syndrome or known family history of Torsades de Pointe.
• Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to starting study treatment.
• Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to New York Heart Association class III or IV congestive heart failure, 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.
• HIV-infected participants who are at a low risk of AIDS-related outcomes may participate in this trial.
• Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (72)

Rocky Mountain Cancer Centers

Denver, Colorado, 80218, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Tulane Uni Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Med Ctr

Boston, Massachusetts, 02215, United States

Location

WA Uni School Of Med

St Louis, Missouri, 63110, United States

Location

Urology Cancer Center PC

Omaha, Nebraska, 68130, United States

Location

Nebraska Cancer Specialists

Omaha, Nebraska, 68154, United States

Location

NYU Laura and Isaac Perlmutter Cancer Center

New York, New York, 10016, United States

Location

Mount Sinai Hosp Med School

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Ctr

New York, New York, 10065, United States

Location

Duke Univ Medical Center

Durham, North Carolina, 27710, United States

Location

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43221, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Uni Of TX MD Anderson Cancer Cntr

Houston, Texas, 77030, United States

Location

Utah Cancer Specialists

Salt Lake City, Utah, 84106, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Onco Hemato Asso of SW Virginia

Roanoke, Virginia, 24014, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Medical College Of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Novartis Investigative Site

Innsbruck, Tyrol, 6020, Austria

Location

Novartis Investigative Site

Linz, 4020, Austria

Location

Novartis Investigative Site

Vienna, 1090, Austria

Location

Novartis Investigative Site

Roeselare, West-Vlaanderen, 8800, Belgium

Location

Novartis Investigative Site

Brussels, 1200, Belgium

Location

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Liège, 4000, Belgium

Location

Novartis Investigative Site

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H2W 1T8, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H3T 1E2, Canada

Location

Novartis Investigative Site

Olomouc, 779 00, Czechia

Location

Novartis Investigative Site

Angers, 49055, France

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Clermont-Ferrand, 63011, France

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Paris, 75970, France

Location

Novartis Investigative Site

Villejuif, 94800, France

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

München, 80377, Germany

Location

Novartis Investigative Site

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Novartis Investigative Site

Maastricht, Limburg, 6229 HX, Netherlands

Location

Novartis Investigative Site

Utrecht, 3584 CX, Netherlands

Location

Novartis Investigative Site

Gliwice, Silesian Voivodeship, 44-101, Poland

Location

Novartis Investigative Site

Bratislava, 83310, Slovakia

Location

Novartis Investigative Site

Santiago Compostela, A Coruna, 15706, Spain

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Novartis Investigative Site

Majadahonda, Madrid, 28222, Spain

Location

Novartis Investigative Site

El Palmar, Murcia, 30120, Spain

Location

Novartis Investigative Site

Pamplona, Navarre, 31008, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46009, Spain

Location

Novartis Investigative Site

Barcelona, 08035, Spain

Location

Novartis Investigative Site

Barcelona, 08036, Spain

Location

Novartis Investigative Site

Barcelona, 08041, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Madrid, 28040, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Málaga, 29010, Spain

Location

Novartis Investigative Site

Seville, 41013, Spain

Location

Novartis Investigative Site

Valencia, 46026, Spain

Location

Novartis Investigative Site

Gothenburg, 413 45, Sweden

Location

Novartis Investigative Site

Lund, 221 85, Sweden

Location

Novartis Investigative Site

Stockholm, 17176, Sweden

Location

Novartis Investigative Site

Baden, 5404, Switzerland

Location

Novartis Investigative Site

Lausanne, 1011, Switzerland

Location

Novartis Investigative Site

Zurich, 8091, Switzerland

Location

Novartis Investigative Site

Guildford, Surrey, GU2 7XX, United Kingdom

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

Coventry, CV2 2DX, United Kingdom

Location

Novartis Investigative Site

London, EC1A 7BE, United Kingdom

Location

Novartis Investigative Site

London, NW1 2BU, United Kingdom

Location

Novartis Investigative Site

London, NW3 2QG, United Kingdom

Location

Novartis Investigative Site

Middlesbrough, TS4 3BW, United Kingdom

Location

Related Publications (2)

• Fizazi K, Morris MJ, Shore ND, Chi KN, Crosby M, de Bono JS, Herrmann K, Roubaud G, Nagarajah J, Fleming M, Lewis B, Nordquist L, Carnahan N, Ghebremariam S, Hertelendi M, Castellano D, Sartor O. Health-related quality of life, pain, and symptomatic skeletal events with [177Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): an open-label, randomised, phase 3 trial. Lancet Oncol. 2025 Jul;26(7):948-959. doi: 10.1016/S1470-2045(25)00189-5. Epub 2025 May 26.

  PMID: 40441170 DERIVED

• Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, Crosby M, Piulats JM, Flechon A, Wei XX, Mahammedi H, Roubaud G, Studentova H, Nagarajah J, Mellado B, Montesa-Pino A, Kpamegan E, Ghebremariam S, Kreisl TN, Wilke C, Lehnhoff K, Sartor O, Fizazi K; PSMAfore Investigators. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024 Sep 28;404(10459):1227-1239. doi: 10.1016/S0140-6736(24)01653-2. Epub 2024 Sep 15.

  PMID: 39293462 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Pluvicto; gallium 68 PSMA-11

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Limitations and Caveats

235 participants were randomized to the AAA617 arm and 234 to the ARDT arm. However, only 228 participants in the AAA617 arm and 232 in the ARDT arm received at least one dose of study treatment. Additionally, 1 participant in the AAA617 arm was excluded from the safety analysis set due to a protocol violation, which means only 227 participants were included in the safety analysis set for this arm.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Patients randomized to ARDT treatment had an option to crossover to 177Lu-PSMA-617 treatment after central confirmation of radiographic progression.

Study Record Dates

• First Submitted: December 9, 2020
• First Posted: December 30, 2020
• Study Start: June 15, 2021
• Primary Completion: October 2, 2022
• Study Completion (Estimated): September 30, 2026
• Last Updated: March 23, 2026
• Results First Posted: October 9, 2025

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (3); PL (1); SL (1); US (20); CZ (1); NL (3); ES (15); SE (3); CH (3); GB (7); FR (6); DE (2); BE (4); CA (3)