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

NCT ID: NCT04689828

Last Updated: 2025-11-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 469 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-15
• Study Completion Date: 2026-09-30

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.

Detailed Description

This is a phase III, open label, multicenter randomized study evaluating the superiority of 177Lu-PSMA-617 over a change of ARDT treatment in prolonging rPFS. The primary endpoint of rPFS is to assess via blinded independent centralized review (BICR) of radiographic images provided by the treating physician and as outlined in PCWG3 modified RECIST v 1.1 Guidelines.

The study also evaluates whether 177Lu-PSMA-617 improves the overall survival (OS) in participants with progressive PSMA-positive mCRPC compared to participants treated with a change in ARDT treatment. OS is defined as the time from randomization to death due to any cause.

Treatment duration: approximately 43 months.

Screening period At screening, the participants are assessed for eligibility and undergo a 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria are randomized.

Randomization period The participants are randomized 1:1 to receive 177Lu-PSMA-617 or a change of the ARDT treatment. The ARDT change includes approved Androgen Receptor (AR) axis targeted therapy (abiraterone or enzalutamide). Supportive care is allowed in both arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. radium-223), poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemi-body radiotherapy treatment is not to be administered during the study treatment period. ARDT is not to be administered concomitantly with 177Lu-PSMA-617. After implementation of Protocol Amendment v4, crossover will be allowed regardless of radiographic progression.

Treatment period • 177Lu-PSMA-617 treatment arm Participants randomized to the investigational arm receive 7.4 GBq +/- 10% of 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT, could be used.

After the last day of study treatment, the participants have to have an End of Treatment (EOT) visit and enter the Post-treatment Follow-up.

• ARDT treatment arm For participants randomized to the ARDT treatment arm, the change of ARDT treatment for each participant is selected by the treating physician prior to randomization and is administered per the physician's orders. Best supportive care, including ADT, could be used. After, the participants have to have an End of Treatment (EOT) and enter the Post-treatment Follow-up.

In absence of safety concerns, every effort should be made to keep the participant on the randomized treatment until BICR-determined radiographic progression (up to implementation of Protocol Amendment v4).

End of Treatment

Randomized treatment may be discontinued if:

• The participant, sponsor or investigator chooses to discontinue treatment
• Toxicity
• Completion of the 6 cycles of 177Lu-PSMA-617
• Serious non-compliance to the protocol
• Disease progression (determined by BICR up to implementation of Protocol Amendment v4)
• Upon implementation of Protocol Amendment v4, participants with ongoing treatment with ARDT will discontinue study drug and either crossover or receive SOC per their treating physician off trial PSA progression is strongly discouraged as a criterion for initiation of a new neoplastic therapy prior to BICR-determined progression. PCWG3 guidelines should be followed to guide discontinuation of treatment End of Treatment visit must be performed ≤ 7 days after the last day of study treatment period. EOT is to occur before the participant ienters the post-treatment Follow-up period of the study and before the initiation of any subsequent anticancer treatment, .

If a participant withdraws consent for the treatment period of the study, an EOT must be done and the participant will enter the Post-treatment Follow-up unless he specifically withdraws post-treatment Follow-up.

Crossover period Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm could either be allowed to crossover to receive 177Lu-PSMA-617 within 28 days of central confirmation of radiographic progression or could continue to receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up.

In order for a participant randomized to the ARDT arm to cross over to receive 177Lu-PSMA-617, he must meet the following criteria:

• Confirmed radiographical progression as assessed by BICR. (After implementation of Protocol Amendment v4, radiographic progression is not required.)
• No intervening antineoplastic therapy is administered after the randomized treatment
• Any unresolved toxicity from prior therapy has to be controlled and can be no greater than CTCAE grade 2 or baseline at the time of registration for crossover.
• ECOG performance status 0-1 at the time of registration for crossover
• Adequate organ function at the time of registration for crossover
• Agreement to continue with the study visit schedule

A participant, who is deemed to have disease progression per investigator assessment, but not by BICR, is not eligible to cross over at that time. Such participant should continue to receive randomized study treatment until progression determined by BICR up to implementation of Protocol Amendment v4.

If crossover to 177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with the same dose/schedule as for participants who were initially randomized to receive 177Lu-PSMA-617 as described above.

After the last day of study treatment period of 177Lu-PSMA-617 or upon second radiographic progression (rPFS2), the participants must have a second End of Treatment (EOT2) visit performed ≤ 7 days and enter the Post-treatment Follow-up. The participant can receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up.

Post-treatment Follow-up period:

• 30-day Safety Follow-up: All randomized and/or treated participants are to have a safety follow-up conducted approximately 30 days after the EOT visit.
• Long term follow-up:

Long term follow-up starts after the 30 Days Safety follow-up and lasts until the patient expires, is lost to follow-up or withdraws consent.

In long term follow-up safety and efficacy information is collected:

• Safety: all medically significant adverse events (all SAEs) deemed to be related to 177Lu-PSMA-617. This includes potential late onset radiation toxicity. For participants who receive 177Lu-PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the following adverse events is captured beyond the 30 day safety period regardless of relationship to study treatment and whether new anticancer therapy has been initiated: hematologic toxicities with primary focus on myelosuppression and thrombocytopenia (including need for transfusion or use of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies. After implementation of Protocol Amendment v4, 177Lu-PSMA-617 exposed participants will be discontinued from the trial once enrolled in the Long-term Safety study.
• Efficacy: Tumor assessments must be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc.) until confirmation of radiographic progression by BICR regardless of whether treatment has been discontinued or new anticancer therapy initiated. After implementation of Protocol Amendment v4, tumor assessments need to continue only for patients actively treated with 177Lu-PSMA-617 as crossover therapy.

The long-term follow-up period also includes the collection of survival information and other assessments.

Other: Other data collected during long-term follow-up includes short physical exam, blood sampling for hematology, chemistry testing, coagulation, DNA and tumor samples for biomarkers. The visits are carried out every 12 weeks (± 28 days) .

Participants who receive 177Lu-PSMA-617 and remain in follow-up on the trial at the sponsor's completion of the study will be asked to join a separate study of long-term safety for a duration of up to 10 years from start of 177Lu-PSMA-617 treatment.

If the participant withdraws consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, information on survival subsequent therapy, and related SAEs is collected.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

177Lu-PSMA-617

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.

Group Type: EXPERIMENTAL

177Lu-PSMA-617

Intervention Type: DRUG

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

68Ga-PSMA-11

Intervention Type: 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).

Androgen receptor-directed therapy (ARDT)

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.

Group Type: ACTIVE_COMPARATOR

68Ga-PSMA-11

Intervention Type: 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).

ARDT

Intervention Type: DRUG

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

Interventions

177Lu-PSMA-617

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

Intervention Type: DRUG

68Ga-PSMA-11

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

Intervention Type: DRUG

ARDT

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

Intervention Type: DRUG

Other Intervention Names

Comparator

Eligibility Criteria

Inclusion Criteria

• 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.
• 11. Participants must have adequate organ function:

• Bone marrow reserve:
• ANC >= 1.5 x 109/L
• Platelets >= 100 x 109/L
• Hemoglobin >= 9 g/dL
• Hepatic:
• Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome =< 3 x ULN is permitted.
• ALT or AST =< 3.0 x ULN OR =< 5.0 x ULN for participants with liver metastases.
• Renal:
• eGFR >= 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation.
• Albumin >= 2.5 g/dL. -. Candidates for change in ARDT as assessed by the treating physician: • Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone.

Exclusion Criteria

• 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.

• Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion.
• 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).
• Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free and treatment free for more than 3 years prior to randomization, are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer.
• Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner.

In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

• Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: Participant with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
• History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study.
• Any condition that precludes raised arms position.
• Eligible for treatment(s) other than ARDT based on presence of any mutations or biomarkers that are known as predictors of better response (e.g., AR-V7 or BRCA).
• Not able to understand and to comply with study instructions and requirements.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Rocky Mountain Cancer Centers

Denver, Colorado, United States

University of Florida

Gainesville, Florida, United States

Tulane Uni Health Sciences Center

New Orleans, Louisiana, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Beth Israel Deaconess Med Ctr

Boston, Massachusetts, United States

WA Uni School Of Med

St Louis, Missouri, United States

Urology Cancer Center PC

Omaha, Nebraska, United States

Nebraska Cancer Specialists

Omaha, Nebraska, United States

NYU Laura and Isaac Perlmutter Cancer Center

New York, New York, United States

Memorial Sloan Kettering Cancer Ctr

New York, New York, United States

Mount Sinai Hosp Med School

New York, New York, United States

Duke Univ Medical Center

Durham, North Carolina, United States

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Uni Of TX MD Anderson Cancer Cntr

Houston, Texas, United States

Utah Cancer Specialists

Salt Lake City, Utah, United States

Virginia Oncology Associates

Norfolk, Virginia, United States

Onco Hemato Asso of SE Virginia

Roanoke, Virginia, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Medical College Of Wisconsin

Milwaukee, Wisconsin, United States

Novartis Investigative Site

Innsbruck, Tyrol, Austria

Novartis Investigative Site

Linz, , Austria

Novartis Investigative Site

Vienna, , Austria

Novartis Investigative Site

Roeselare, West-Vlaanderen, Belgium

Novartis Investigative Site

Brussels, , Belgium

Novartis Investigative Site

Ghent, , Belgium

Novartis Investigative Site

Liège, , Belgium

Novartis Investigative Site

Vancouver, British Columbia, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Olomouc, , Czechia

Novartis Investigative Site

Angers, , France

Novartis Investigative Site

Bordeaux, , France

Novartis Investigative Site

Clermont-Ferrand, , France

Novartis Investigative Site

Lyon, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Villejuif, , France

Novartis Investigative Site

Essen, , Germany

Novartis Investigative Site

München, , Germany

Novartis Investigative Site

Nijmegen, Gelderland, Netherlands

Novartis Investigative Site

Maastricht, Limburg, Netherlands

Novartis Investigative Site

Utrecht, , Netherlands

Novartis Investigative Site

Gliwice, Silesian Voivodeship, Poland

Novartis Investigative Site

Bratislava, , Slovakia

Novartis Investigative Site

Santiago Compostela, A Coruna, Spain

Novartis Investigative Site

L'Hospitalet de Llobregat, Barcelona, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Majadahonda, Madrid, Spain

Novartis Investigative Site

El Palmar, Murcia, Spain

Novartis Investigative Site

Pamplona, Navarre, Spain

Novartis Investigative Site

Valencia, Valencia, Spain

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Málaga, , Spain

Novartis Investigative Site

Seville, , Spain

Novartis Investigative Site

Valencia, , Spain

Novartis Investigative Site

Gothenburg, , Sweden

Novartis Investigative Site

Lund, , Sweden

Novartis Investigative Site

Stockholm, , Sweden

Novartis Investigative Site

Baden, , Switzerland

Novartis Investigative Site

Lausanne, , Switzerland

Novartis Investigative Site

Zurich, , Switzerland

Novartis Investigative Site

Guildford, Surrey, United Kingdom

Novartis Investigative Site

Sutton, Surrey, United Kingdom

Novartis Investigative Site

Coventry, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Middlesbrough, , United Kingdom

Countries

United States; Austria; Belgium; Canada; Czechia; France; Germany; Netherlands; Poland; Slovakia; Spain; Sweden; Switzerland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 40441170 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 39293462 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2023-507772-50-00

Identifier Type: OTHER

Identifier Source: secondary_id

CAAA617B12302

Identifier Type: -

Identifier Source: org_study_id