Intrinsic Validity of Molecular Marker(s) Detection on Tissular Tumoral DNA to Predict the Efficacy of 177Lutetium-PSMA-617 (Lu-PSMA) Treatment for Castration-resistant Metastatic Prostate Cancer (PSMA-PRED)

Intrinsic Validity of Molecular Marker(s) Detection on Tissular Tumoral DNA to Predict the Efficacy of 177Lutetium-PSMA-617 (Lu-PSMA) Treatment for Castration-resistant Metastatic Prostate Cancer (PSMA-PRED)

Prostate cancer is the most common cancer in men. Its incidence is rising as the population ages. In the localized stage, the 5-year overall survival rate (OS) is 98%. Metastatic progression and resistance to castration have a negative impact on prognosis. Despite recent advances in management, the 5-year OS is around 30%. Therapeutic advances in this indication have been made mainly by the use of taxanes and second-generation hormone therapy. These treatments have improved OS and progression-free survival (PFS). They are now used as standard therapy.

More recently, the Phase III VISION trial confirmed the improvement in OS and radiological PFS achieved by treatment with the radioligand 177Lutetium-PSMA-617 (Lu-PSMA) in patients with advanced metastatic castration-resistant prostate cancer (mCRPC).

This treatment is currently available in early access in France. Despite encouraging results, 40% of patients will not respond to Lu-PSMA, and there are currently no validated predictive factors. Studies are currently on going, but the identification of biomarkers seems necessary to better stratify risk in these patients.

Numerous tissue prognostic tests based on molecular characteristics or cell proliferation are emerging with this in mind. At present, molecular profiling is not a routine technique for prostate cancer, as it is for other solid cancers. At an early stage, the Decipher® Genomic classification tool has shown prognostic utility independently of therapeutic and clinico-pathological data.

According to recent studies, methylome analysis would enable the subdivision of mCRPCs and could help identify new therapeutic targets.

In the metastatic phase, certain molecular abnormalities involving DNA repair genes are predictive of response to PARP inhibitors.

Molecular analysis (mutations, copy number alterations, gene expression, DNA methylation) could therefore be useful in optimizing the management of mCRPC patients treated with Lu-PSMA.

If reliable molecular abnormalities are identified on tissue, a diagnostic technique based on circulating tumor DNA (ctDNA) analysis will be useful in decision-making for these patients. A biological collection will therefore be created during the course of this study, with a view to using ctDNA analysis in subsequent research.

Study Overview

• Status: Recruiting
• Conditions: Castration-resistant Metastatic Prostate Cancer; Treated by 177Lutetium-PSMA-617 (Lu-PSMA)
• Intervention / Treatment: Biological: Blood samples

Detailed Description

Prostate cancer is the most common cancer in men. Its incidence is rising as the population ages. In the localized stage, the 5-year overall survival rate (OS) is 98%. Metastatic progression and resistance to castration have a negative impact on prognosis. Despite recent advances in management, the 5-year OS is around 30%. Therapeutic advances in this indication have been made mainly by the use of taxanes and second-generation hormone therapy. These treatments have improved OS and progression-free survival (PFS). They are now used as standard therapy.

More recently, the Phase III VISION trial confirmed the improvement in OS and radiological PFS achieved by treatment with the radioligand 177Lutetium-PSMA-617 (Lu-PSMA) in patients with advanced metastatic castration-resistant prostate cancer (mCRPC).

This treatment is currently available in early access in France. Despite encouraging results, 40% of patients will not respond to Lu-PSMA, and there are currently no validated predictive factors. Studies are currently on going, but the identification of biomarkers seems necessary to better stratify risk in these patients.

Numerous tissue prognostic tests based on molecular characteristics or cell proliferation are emerging with this in mind. At present, molecular profiling is not a routine technique for prostate cancer, as it is for other solid cancers. At an early stage, the Decipher® Genomic classification tool has shown prognostic utility independently of therapeutic and clinico-pathological data.

According to recent studies, methylome analysis would enable the subdivision of mCRPCs and could help identify new therapeutic targets.

In the metastatic phase, certain molecular abnormalities involving DNA repair genes are predictive of response to PARP inhibitors.

Molecular analysis (mutations, copy number alterations, gene expression, DNA methylation) could therefore be useful in optimizing the management of mCRPC patients treated with Lu-PSMA.

If reliable molecular abnormalities are identified on tissue, a diagnostic technique based on circulating tumor DNA (ctDNA) analysis will be useful in decision-making for these patients. A biological collection will therefore be created during the course of this study, with a view to using ctDNA analysis in subsequent research.

This is an interventional, multi-center study. The study is prospective, single-arm, open-label and non-randomized.

Its primary objective is to identify biomarkers of interest, in primary tissue, predictive of response to Lu-PSMA treatment in patients with mCRPC, through the detection of molecular abnormalities in DNA/RNA and methyloma.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Judith PASSILDAS JAHANMOHAN, PhD; Phone Number: 0473278005; Email: judith.passildas@clermont.unicancer.fr

Study Locations

• France
  • Clermont-Ferrand, France, 63011
    • Recruiting
    • Centre Jean Perrin
    • Contact: Judith PASSILDAS JAHANMOHAN, PhD; Phone Number: 0473278005; Email: judith.passildas@clermont.unicancer.fr
    • Principal Investigator: Tressie HERRMANN, Dr
  • La Tronche, France, 38700
    • Not yet recruiting
    • CHU de Grenoble
    • Principal Investigator: Loic DJAILEB, Dr
  • Pierre-Bénite, France, 69310
    • Not yet recruiting
    • Hospices Civiles de Lyon
    • Principal Investigator: Denis MAILLET, Dr
  • Saint-Etienne, France, 42100
    • Not yet recruiting
    • Hôpital Privé de la Loire
    • Principal Investigator: Aline GUILLOT, Dr
  • Strasbourg, France, 67091
    • Not yet recruiting
    • Centre Paul Strauss
    • Principal Investigator: Francois SOMME, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male >18 years of age
• ECOG ≤ 2
• Patient with histologically confirmed of metastatic castration resistant prostatic adenocarcinoma and with tumor biological material available (prostatic biopsies or prostatectomy)
• Patient who received at least one taxane line and a second generation hormone therapy line
• Patient receiving androgen deprivation therapy with serum testosterone < 50 ng/dL or < 1.7 nmol/L or having undergone surgical castration

• Progressive mCRPC based based on at least 1 of the following criteria :

  • Serum or plasma PSA progression defined as 2 consecutive increases in PSA measured at least 1 week prior. The minimal start value is 2.0 ng/mL ; 1,0 ng/mL is the minimal start value if confirmed increase in PSA is the only indication of progress
  • Soft-tissue progression by RECIST 1.1 criteria
  • Progression of bone disease : two new lesions ; only the positivity of bone scan defines metastatic bone disease, according to PCWG3 criteria.

• Patients with at least one metastasis, bone and/or soft tissue and/or visceral, documented by the following methods in the 43 days prior to inclusion :

  • Bone metastasis (regardless of location) highlighted by bone scan AND/OR
  • Lymph nodes metastasis, regardless of size and location; if the metastasis are only lymph nodes, the short axis of at least one node should be at least 15 mm AND outside the pelvis ; AND/OR
  • Visceral metastasis, regardless of size and location; a history of visceral metastasis at any time prior to randomization should be encoded as the presence of visceral metastasis at baseline (i.e., a patient with visceral metastasis prior ADT introduction which are disappeared at baseline will be counted as having visceral metastasis and will be considered to have a high tumor volume during stratification)

• Patient with Lu-PSMA treatment indication, confirmed by PET 68Ga-PSMA-11. Eligibility for 68Ga-PSMA-11 PET is defined as:

  • At least one lesion with a binding intensity greater than that of the liver parenchyma (definition of positivity),
  • All lymph node lesions larger than 25 mm in the short axis must be positive on PSMA PET
  • All bone metastases with a soft tissue component ≥ 10 mm in the largest diameter must be positive on PSMA-PET
  • All solid organ metastases (e.g., lung, liver, adrenal glands, etc.) ≥ 10 mm in the largest diameter must be positive on PSMA-PET.

• Adequate organ function :

  • Bone marrow reserve :

    • Absolute neutrophil count ≥ 1.5 x 10^9/L
    • Platelets ≥ 100 x 10^9/L.
    • Hemoglobin ≥ 9 g/dL

  • Hepatic function :

    • Total bilirubin ≤ 2 x the upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤ 3 x ULN is permitted.
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases.
    • Albumin > 2.5 g/dL
  • Renal function : Glomerular Filtration Rate (GFR) ≥ 50 mL/min/1.73m2 according to MDRD equation.
• Obtaining the patient's free and informed consent
• Social security scheme or beneficiary.

Exclusion Criteria :

• Continuation of second-generation hormone therapy Patient
• Other cancer in the last 3 years likely to change life expectancy or interfere with the assessment of the disease
• Protected adult
• History of somatic or psychiatric illness/condition that may interfere with study objectives and evaluations
• Patient unable to understand and comply with study instructions and requirements
• ECOG > 2
• Dilation of pyelocalicial cavities not previously supported
• Obstruction of bladder discharge or uncontrollable and simultaneous urinary incontinence
• Symptomatic spinal cord compression or clinical or radiological findings indicating imminent spinal cord compression
• Fractured risk of bone damage
• Active and symptomatic brain injury
• Concurrent participation in a therapeutic trial and administration of any investigational agent within 28 days of inclusion
• Metastatic tumor tissue as the only material available for prostate cancer diagnosis
• Previous treatment with any of the following in the 6 months prior to inclusion : Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-cyclic irradiation
• Previous treatment with radioligands targeting PSMA
• Known hypersensitivity to one of the study treatments or its excipients or similar class drugs
• Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for inclusion in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional; Genetic analysis will be conducted on intial tumor sample in order to identify biomarkers	Biological: Blood samples; A total of 3 blood samples (2 tubes of 9mL each) are added. The first sample will be taken at the inclusion visit, the 2nd at the end of the 2nd treatment cycle and the last at the end of Lu-PSMA treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular abnormalities retained on primary tumor sample predicting response to Lu-PSMA in metastatic castration resistant prostate cancer patients assessed according to RECIST 1.1 and/or PCWG3 criteria	Biological interpretation and response to Lu-PSMA treatment on bone scan and CT scan according to RECIST 1.1 and/or PCWG3 criteria	From enrollment to 24 months after Lu-PSMA treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between biomarker(s) (molecular abnormalities retained on primary tumor sample for the first outcome measure) and survival without radiological progression	Radiological progression free survival defined as the duration between the start date of treatment and the date of the first progression of the disease according to criteria RECIST V1.1 and criteria PCWG3; or the date of death whatever the cause.	From enrollment to 24 months after Lu-PSMA treatment
Correlation between biomarker(s) (molecular abnormalities retained on primary tumor sample for the first outcome measure) and survival without biological progression	Biological progression free survival defined as the duration between the start date of treatment and the date of the first PSA progression	From enrollment to 24 months after Lu-PSMA treatment
Correlation between biomarker(s) (molecular abnormalities retained on primary tumor sample for the first outcome measure) and survival without clinical progression	Clinical progression free survival, definieds as the duration between the treatment start date and the date of the first clinical progression	From enrollment to 24 months after Lu-PSMA treatment
Correlation between biomarker(s) (molecular abnormalities retained on primary tumor sample for the first outcome measure) and overall survival	Overall survival definied as the time interval between the start date of treatment and the date of death whatever the cause	From enrollement to the end of the study, up to 58 months
Correlation between the biomarker(s) (molecular abnormalities retained on primary tumor sample for the first outcome measure) and adverse effects during treatment.	Toxicities related to treatment of grade 3 or higher according to CTCAE v. 5.0 and any EIG	From enrollment to the end of Lu-PSMA treatment, up to 58 months
Assess whether consideration of clinical characteristics improves biomarker performance	Performance status (0 to 4), pain and adverse events evaluations as assessed by CTCAE v4.0	From enrollement to end of Lu-PSMA treatment, up to 58 months
Assess whether consideration of radiological characteristics improves biomarker performance	Radiological evaluation as assessed by RECIST criteria V1.1 and PCWG3 criteria	From enrollement to end of Lu-PSMA treatment, up to 58 months
Assess whether consideration of biological characteristics improves biomarker performance	Biological evaluation as assessed with PSA level	From enrollement to end of Lu-PSMA treatment, up to 58 months
Biological interpretation and response to Lu-PSMA treatment on PET scan	Radiological progression free survival defined as the duration between the start date of treatment according to RECIP 1.0 criteria for patients who underwent 68Ga-PSMA-11 PET scans	From enrollment to 24 months after Lu-PSMA treatment

Collaborators and Investigators

• Sponsor: Centre Jean Perrin
• Collaborators: GIRCI Auvergne Rhone-Alpes

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2024
• Primary Completion (Estimated): June 30, 2034
• Study Completion (Estimated): June 30, 2034

Study Registration Dates

• First Submitted: July 22, 2024
• First Submitted That Met QC Criteria: September 13, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 26, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: biomarkers; response; mCRPC; prediction; Lu-PSMA
• 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; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: 2024-A00246-41

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No