Clinical trial NCT06496581: Standard of Care +/- 177Lu-PSMA-617 In de Novo mHSPC Patients With Poor PSA Response (PEACE6-Poor Responders)
Official title: A Randomized Phase III Trial Evaluating the Efficacy and Safety of Standard of Care +/- 177Lu-PSMA617 in de Novo Metastatic Hormone-sensitive Prostate Cancer Patients Having a PSA≥0.2 ng/mL at 6-8 Months After Systemic Treatment Initiation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer Metastatic
Keywords: Genital Diseases, Male
Prostatic Diseases
Hormones
177Lu-PSMA-617
PSA
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2024-07-11
Enrollment: 500
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, international, multicenter, randomized
Primary purpose: TREATMENT

Brief summary: PEACE-6 Poor Responders is an international, multicenter, open-label, controlled, randomized, phase III trial to evaluate the efficacy and safety of 177Lu-PSMA-617 when administered on top of the ongoing standard systemic treatment compared to standard systemic treatment alone in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who do not present with a satisfactory response characterized by a serum prostatic specific antigen (PSA) level of ≥ 0.2 ng/mL at 6 to 8 months after systemic treatment initiation for mHSPC (i.e. poor responders) in the absence of evidence of cancer progression (including a rising PSA level).

Detailed description: The study plans to enroll 500 patients over 63 months who will be randomized (1:1) to receive either: (i) Control arm: SoC (ADT+ ARSI (second-generation androgen receptor signaling inhibitors) +/- RT or ADT+ ARSI +/- RT) or (ii) Experimental arm: 177Lu-PSMA-617 + SoC (ADT+ ARSI +/- RT or ADT+ docetaxel + ARSI +/- RT). Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Treatment will be continued at least until castration-resistant prostate cancer (CRPC) stage is reached, defined by evidence of cancer progression (either a confirmed PSA rise or a radiographic progression) with serum testosterone being at castrated levels (\<0.50 ng/mL). This systemic treatment may be continued after CRPC is reached, based on patient benefit and the investigator's opinion. Treatment may also be terminated at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient, including: unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient request. At the end of treatment period, the follow-up period will last for 102 months (8.5 years). The overall trial duration, including the follow-up, is expected to last 18.5 years.

Eligibility criteria: Inclusion Criteria:

All of the following criteria must be met ahead of randomization to satisfy trial eligibility requirements:

1. Signed a written informed consent form prior to any trial specific procedures.

   Note: In case of physical incapacitation, a trusted representative of their choice, which is not the Investigator or sponsor, can sign on the behalf of the patients.
2. Aged ≥18 years old
3. Life expectancy \> 6 months as per investigator estimate
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
5. Men with histologically or cytologically confirmed adenocarcinoma of the prostate
6. De novo metastatic disease defined by clinical or radiographic evidence of metastases at diagnosis (i.e. before any treatment started). If not available, a more recent imaging can be used
7. Measurable disease or bone lesions evaluable according to PCWG3 criteria. Patients with doubtful bone metastases are not eligible
8. A pre-randomization 68Ga-PSMA-11 PET/CT scan performed within 4 weeks prior to randomization in the trial.

   FDG PET scan is not required for this protocol. All patients will be treated independently from the results of pre-randomization PSMA PET scan: patients with PSMA-positive or PSMA-negative disease according to PROMISE 2.0 criteria are eligible.
9. Have 6 to 8 months of previous AND ongoing standard systemic treatment for prostate cancer consisting in either:

   * ADT with an androgen receptor signaling inhibitor (ARSI) (i.e., abiraterone (plus prednisone), or apalutamide or enzalutamide) ± radiotherapy \*\*
   * ADT with docetaxel\* plus an ARSI (i.e. abiraterone (plus prednisone), or darolutamide,) ± radiotherapy\*\*

   Note:

   \*Docetaxel must have been stopped at least 4 weeks ahead of randomization.

   \*\* Previous radiotherapy to the primary tumor and/or to the metastases is accepted as long as it was not PSMA-based and must has been completed at least 4 weeks ahead of randomization.
10. Stable or declining PSA level but not a rising one
11. Serum PSA of ≥ 0.2 ng/mL at 6 to 8 months after systemic treatment initiation
12. Testosterone level \< 50 ng/dl or \< 1.7 nmol/L
13. Be fit enough for 177Lu-vipivotide tetraxetan treatment:

    * Adequate bone marrow function: hemoglobin ≥90 g/L (in absence of red blood cell transfusion within 4 weeks prior to randomization), absolute neutrophil count ≥1.5 x10⁹/L, platelet count \>100 x10⁹/L
    * Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0 x upper limit of normal (ULN), or ≤ 5.0 x ULN in the presence of liver metastases; bilirubin \<1.5 x ULN (unless known or suspected Gilbert syndrome, then \<3 x ULN is permitted)
    * Adequate renal function: calculated creatinine clearance ≥ 50 ml/min (using the MDRD or CKD EPI method).
14. For sexually active men with female partners of reproductive potential or with pregnant women, agreement to use a condom with another effective contraceptive method during trial participation and up to 14 weeks after study treatment completion.
15. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).
16. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion Criteria:

Patients presenting with any of the following criteria are not eligible:

1. Any evidence of cancer progression (including a rising PSA level, clinical progression, or radiological progression)
2. Prior or concurrent PSMA-based radioligand therapy or other PSMA target treatments
3. Known hypersensitivity to the components of the study therapy or its analogs
4. Any condition preventing the use of the standard of care and/or specific experimental treatments tested in the trial
5. Any of the following within 6 months before randomization: stroke, myocardial infraction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) Class III or IV
6. Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure \[sBP\] ≥ 160 mmHg or diastolic blood pressure \[dBP\] ≥ 95 mmHg, 3 consecutive measures taken 5 minutes apart)
7. Severe or uncontrolled concurrent disease, infection or co-morbidity
8. Pathological findings consistent with small cell carcinoma of the prostate
9. History of malignancy within 3 years of the current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma
10. Ongoing participation in another clinical trial involving an investigational product.. Treatment with an investigational product must have ended within 28 days prior to the day of randomization
11. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
12. Persons deprived of their liberty or under protective custody or guardianship

Primary outcomes:
measure: Overall survival (OS)
timeFrame: From randomization to death due to any cause, up to 8.5 years
measure: Radiographic progression-free survival (rPFS)
timeFrame: From randomization to radiographic progression or death, up to 8.5 years
Secondary outcomes:
measure: Castration-Resistance Prostate Cancer-Free Survival (CRPC-FS)
timeFrame: From randomization to onset of castration-resistance or death, up to 8.5 years
measure: Prostate Cancer-Specific Survival (PCSS)
timeFrame: From the date of randomization to a PCSS event, up to 8.5 years
measure: PSA response
timeFrame: From baseline over the treatment period, up to 8.5 years
measure: Skeletal-related event-free survival (SRE-FS)
timeFrame: From randomization to the onset of a SRE-FS event, up to 8.5 years
measure: Time to severe urinary event (SUE)
timeFrame: From randomization to the onset of a SUE event, up to 8.5 years
measure: Time to initiation of first subsequent anti-cancer systemic therapy for CRPC (TTSST1)
timeFrame: From randomization to initiation of the first anti-cancer systemic therapy for CRPC, up to 10 years
measure: Time to initiation of second subsequent anti-cancer systemic therapy for CRPC (TTSST2)
timeFrame: From randomization to initiation of the second anti-cancer systemic therapy for CRPC, up to 10 years
measure: Efficacy of first subsequent anti-cancer systemic therapy for CRPC
timeFrame: From first anti-cancer systemic therapy for CRPC to disease progression or death, up to 10 years
measure: Efficacy of second subsequent anti-cancer systemic therapy for CRPC
timeFrame: Fromsecond anti-cancer systemic therapy for CRPC to disease progression or death, up to 10 years
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHRU Brest
city: Caen
country: France
facility: Centre Francois Baclesse
city: Créteil
country: France
facility: CHU Henri Mondor
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Grenoble
country: France
facility: CHU Grenoble
city: Lyon
country: France
facility: Centre Léon Berard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Nancy
country: France
facility: CHRU Nancy
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Institut Curie
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Cloud
country: France
facility: Institut Curie
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Saint-Priest-en-Jarez
country: France
facility: CHU Saint Etienne
city: Strasbourg
country: France
facility: ICANS
city: Toulouse
country: France
facility: IUCT Oncopole
city: Tours
country: France
facility: CHRU Tours
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Gustave Roussy, Villejuif
name: Karim FIZAZI, MD
role: STUDY_CHAIR
affiliation: IPC, Marseille
name: Gwenaelle GRAVIS, MD
role: STUDY_CHAIR
References: